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Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib

Omar S Usmani,1 Nicolas Roche,2 Martin Jenkins,3 Neda Stjepanovic,4 Peter Mack,5 Wilfried De Backer6 1National Heart and Lung Institute (NHLI), Imperial College London, and Royal Brompton Hospital, London, UK; 2Respiratory Medicine, Cochin Hospital, University Paris Descartes, Paris, France; 3AstraZeneca, Cambridge, UK; 4AstraZeneca, Gothenburg, Mölndal, Sweden; 5AstraZeneca, Durham, NC, USA; 6Department of Pulmonary Medicine, Faculty of Medicine, University of Antwerp, Antwerp, BelgiumCorrespondence: Wilfried De BackerDepartment of Pulmonary Medicine, Faculty of Medicine, University of Antwerp, Lange Lozanastraat 142, Antwerp 2018, BelgiumTel +32 468 195206Email wilfried.debacker@uantwerpen.beAbstract: Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug–drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The AerosphereTM inhaler, formulated using co-suspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.Keywords: Aerosphere, BGF MDI, co-suspension delivery technology, FRI, GFF MDI, metered dose inhaler

Glenn Leemans,1,2 Dennis Belmans,2 Cedric Van Holsbeke,2 Vladimir Kushnarev,3 Jason Sugget,3 Kris Ides,1 Dirk Vissers,1 Wilfried De Backer4 1Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Wilrijk, Belgium; 2FLUIDDA nv, Antwerp, Kontich, Belgium; 3Trudell Medical International, London, Ontario, Canada; 4Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Wilrijk, BelgiumCorrespondence: Glenn LeemansFaculty of Medicine and Health Sciences University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, BelgiumTel +32 495 34 84 59Email glenn.leemans@uantwerpen.bePurpose: Chronic obstructive pulmonary disease (COPD) patients are prone to suffer from chronic bronchitis, which ultimately affects their quality of life and overall prognosis. Oscillating positive expiratory pressure (oPEP) devices are designed to aid in the mucus clearance by generating positive pressure pulses in the airways. The main aim of this study was to analyze the impact of a specific oPEP device – Aerobika® – on top of standard of care medication in COPD patients’ lung dynamics and drug deposition.Patients and Methods: In this single-arm pilot study, patients were assessed using standard spirometry tests and functional respiratory imaging (FRI) before and after a period of 15± 3 days of using the oPEP device twice daily (before their standard medication).Results: The utilization of the oPEP device led to a significant increase of 2.88% in specific airway volume after two weeks (1.44 (SE: 0.18) vs 1.48 (SE: 0.19); 95% CI = [0.03%,5.81%]; p=0.048). Moreover, the internal airflow distribution (IAD) was affected by the treatment: patients’ changes ranged from − 6.74% to 4.51%. Furthermore, IAD changes at the lower lobes were also directly correlated with variations in forced expiratory volume in one second and peak expiratory flow; conversely, IAD changes at the upper lobes were inversely correlated with these clinical parameters. Interestingly, this change in IAD was significantly correlated with changes in lobar drug deposition (r2=0.30, p< 0.001).Conclusion: Our results support that the Aerobika device utilization leads to an improved airflow, which in turn causes a shift in IAD and impacts the drug deposition patterns of the concomitant medication in patients with COPD.Keywords: mucus hypersecretion, airway clearance techniques, functional respiratory imaging, internal airflow distribution, drug deposition

Wilfried De Backer,1 Jan De Backer,2 Wim Vos,3 Ilse Verlinden,3 Cedric Van Holsbeke,3 Johan Clukers,1 Bita Hajian,1 Shahid Siddiqui,4 Martin Jenkins,5 Colin Reisner,4,6 Ubaldo J Martin4 1Department of Respiratory Medicine, University of Antwerp, Antwerp, Belgium; 2FLUIDDA, Los Angeles, CA, USA; 3FLUIDDA, Kontich, Belgium; 4AstraZeneca, Gaithersburg, MD, USA; 5AstraZeneca, Cambridge, UK; 6Pearl – A member of the AstraZeneca Group, Morristown, NJ, USA Background: Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance. Patients and methods: In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 µg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography). Results: Twenty patients (46–78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P

Wouter H van Geffen,1,2 Bita Hajian,3 Wim Vos,4 Jan De Backer,4 Anthony Cahn,5 Omar S Usmani,6 Cedric Van Holsbeke,4 Massimo Pistolesi,7 Huib AM Kerstjens,2 Wilfried De Backer3 1Department of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, the Netherlands; 2Department of Pulmonary Diseases, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, the Netherlands; 3Department of Pulmonary Diseases, Antwerp University Hospital, Antwerp, Belgium; 4FLUIDDA nv, Kontich, Belgium; 5GlaxoSmithKline R&D, Stevenage, UK; 6Faculty of Medicine, National Heart & Lung Institute, Imperial College London, London, UK; 7Department of Experimental and Clinical Medicine, Section of Respiratory Medicine, University of Florence, Florence, Italy Background: Exacerbations of COPD are a major burden to patients, and yet little is understood about heterogeneity. It contributes to the current persistent one-size-fits-all treatment. To replace this treatment by more personalized, precision medicine, new insights are required. We assessed the heterogeneity of exacerbations by functional respiratory imaging (FRI) in 3-dimensional models of airways and lungs. Methods: The trial was designed as a multicenter trial of patients with an acute exacerbation of COPD who were assessed by FRI, pulmonary function tests, and patient-reported outcomes, both in the acute stage and during resolution. Results: Forty seven patients were assessed. FRI analyses showed significant improvements in hyperinflation (a decrease in total volume at functional residual capacity of -0.25±0.61 L, p≤0.01), airway volume at total lung capacity (+1.70±4.65 L, p=0.02), and airway resistance. As expected, these improvements correlated partially with changes in the quality of life and in conventional lung function test parameters. Patients with the same changes in pulmonary function differ in regional disease activity measured by FRI. Conclusion: FRI is a useful tool to get a better insight into exacerbations of COPD, and significant improvements in its indices can be demonstrated from the acute phase to resolution even in relatively small groups. It clearly visualizes the marked variability within and between individuals in ventilation and resistance during exacerbations and is a tool for the assessment of the heterogeneity of COPD exacerbations. Keywords: COPD exacerbations, FRI, hyperinflation, chronic obstructive pulmonary disease, symptoms, heterogeneity

Bita Hajian,1 Jan De Backer,2 Wim Vos,2 Wouter H van Geffen,3 Paul De Winter,1 Omar Usmani,4 Tony Cahn,5 Huib AM Kerstjens,3 Massimo Pistolesi,6 Wilfried De Backer1 1Department of Respiratory Medicine, University Hospital Antwerp, Edegem, Belgium; 2FLUIDDA nv, Kontich, Belgium; 3Department of Respiratory Medicine, University Medical Center Groningen, Groningen, the Netherlands; 4Department of Pulmonology, Brompton Hospital, London, UK; 5GSK, London, UK; 6Department of Pulmonary Diseases, University of Firenze, Florence, Italy Introduction: Severe exacerbations associated with chronic obstructive pulmonary disease (COPD) that require hospitalization significantly contribute to morbidity and mortality. Definitions for exacerbations are very broad, and it is unclear whether there is one predominant underlying mechanism that leads to them. Functional respiratory imaging (FRI) with modeling provides detailed information about airway resistance, hyperinflation, and ventilation–perfusion (V/Q) mismatch during and following an acute exacerbation. Materials and methods: Forty-two patients with COPD participating in a multicenter study were assessed by FRI, pulmonary function tests, and self-reported outcome measures during an acute exacerbation and following resolution. Arterial blood gasses and lung function parameters were measured. Results: A significant correlation was found between alveolar–arterial gradient and image-based V/Q (iV/Q), suggesting that iV/Q represents V/Q mismatch during an exacerbation (p

Bita Hajian,1 Jan De Backer,2 Claire Sneyers,3 Francisca Ferreira,2 Katherine C Barboza,2 Glenn Leemans,1 Wim Vos,2 Wilfried De Backer1 1Department of Respiratory Medicine, University Hospital Antwerp, 2FLUIDDA nv, 3Department of Physical Medicine, Monica Hospital, Antwerp, Belgium Introduction: Patients with severe COPD often develop chronic hypercapnic respiratory failure. Their prognosis worsens and they are more likely to develop exacerbations. This has major influence on the health-related quality of life. Currently, there is no information about the success of long-term noninvasive ventilation (NIV) among patients who receive NIV in acute settings. Also, little is known about the pathophysiological mechanism of NIV. Methods: Ten Global Initiative for Obstructive Lung Disease stage III and IV COPD patients with respiratory failure who were hospitalized following acute exacerbation were treated with NIV using a Synchrony BiPAP device for 6 months. Arterial blood gases and lung function parameters were measured. Low-dose computed tomography of the thorax was performed and used for segmentation. Further analyses provided lobe volume, airway volume, and airway resistance, giving an overall functional description of the separate airways and lobes. Ventilation perfusion (VQ) was calculated. Patient-reported outcomes were evaluated. Results: PaCO2 significantly improved from 50.03 mmHg at baseline to 44.75 mmHg after 1 month and 43.37 mmHg after 6 months (P=0.006). Subjects showed improvement in the 6-minute walk tests (6MWTs) by an average of 51 m (from 332 m at baseline to 359 m at 1 month and 383 m at 6 months). Patients demonstrated improvement in self-reported anxiety (P=0.018). The improvement in image-based VQ was positively associated with the 6MWT and the anxiety domain of the Severe Respiratory Insufficiency Questionnaire. Conclusion: Though previous studies of long-term NIV have shown conflicting results, this study demonstrates that patients can benefit from long-term NIV treatment, resulting in improved VQ, gas exchange, and exercise tolerance. Keywords: noninvasive ventilation, COPD, functional respiratory imaging, ventilation perfusion, BiPAP, hypercapnia, exacerbations

Bita Hajian,1 Jan De Backer,2 Wim Vos,2 Cedric Van Holsbeke,2 Francisca Ferreira,2 Deborah A Quinn,3 Annemie Hufkens,1 Rita Claes,1 Wilfried De Backer1 1Department of Respiratory Medicine, University Hospital Antwerp, Edegem, 2FluidDA nv, Antwerp, Belgium; 3Bellerophon Therapeutics, Warren, NJ, USA Introduction: Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI). Methods: Six patients with secondary PH due to COPD received “pulsed” iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. Results: Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω20=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. Conclusion: Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted. Keywords: pulmonary hypertension, COPD, pulsed inhaled nitric oxide, FRI

Wim Vos,1 Bita Hajian,2 Jan De Backer,1 Cedric Van Holsbeke,1 Samir Vinchurkar,1 Rita Claes,2 Annemie Hufkens,2 Paul M Parizel,3 Lieven Bedert,4 Wilfried De Backer2 1FLUIDDA nv, Groeningenlei, Kontich, 2Department of Respiratory Medicine, 3Department of Radiology, University Hospital Antwerp, Wilrijkstraat, Edegem, 4Department of Respiratory Medicine, ZNA Middelheim Hospital, Antwerp, Belgium Background: Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs).Methods: Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively.Results: The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=−2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=−5.368, P

A rapid data-driven method for determining regional deposition of inhaled medication aerosols in human airways is presented, which is patient specific. Inhalation patterns, device characteristics, and aerodynamic particle size distribution of medications are considered. The method is developed using dimensional analysis and Buckingham Pi theorem, and provides total, regional, and lobar distributions of aerosol deposition. 34 dimensionless quantities are selected, of which 22 encode features of the airway trees and segmented lobes, 14 pertain to the device and the drug formulation, and 13 the inhalation profile of the subject. The dimensionless correlations are obtained using a large database of computational fluid dynamics results on patient specific airways. The intraclass correlation coefficient between the current method and its training dataset is 0.92. The difference between the predicted average lobar deposition in the six asthma patients and the in-vivo data is 1.3%. The model has the potential to offer insights into the effectiveness of personalized drug delivery in clinical settings and can aid in drug development cycles., (© 2024. The Author(s).)

Background: Computer Aided Lung Sound Analysis (CALSA) aims to overcome limitations associated with standard lung auscultation by removing the subjective component and allowing quantification of sound characteristics. In this proof-of-concept study, a novel automated approach was evaluated in real patient data by comparing lung sound characteristics to structural and functional imaging biomarkers., Methods: Patients with cystic fibrosis (CF) aged > 5y were recruited in a prospective cross-sectional study. CT scans were analyzed by the CF-CT scoring method and Functional Respiratory Imaging (FRI). A digital stethoscope was used to record lung sounds at six chest locations. Following sound characteristics were determined: expiration-to-inspiration (E/I) signal power ratios within different frequency ranges, number of crackles per respiratory phase and wheeze parameters. Linear mixed-effects models were computed to relate CALSA parameters to imaging biomarkers on a lobar level., Results: 222 recordings from 25 CF patients were included. Significant associations were found between E/I ratios and structural abnormalities, of which the ratio between 200 and 400 Hz appeared to be most clinically relevant due to its relation with bronchiectasis, mucus plugging, bronchial wall thickening and air trapping on CT. The number of crackles was also associated with multiple structural abnormalities as well as regional airway resistance determined by FRI. Wheeze parameters were not considered in the statistical analysis, since wheezing was detected in only one recording., Conclusions: The present study is the first to investigate associations between auscultatory findings and imaging biomarkers, which are considered the gold standard to evaluate the respiratory system. Despite the exploratory nature of this study, the results showed various meaningful associations that highlight the potential value of automated CALSA as a novel non-invasive outcome measure in future research and clinical practice., (© 2024. The Author(s).)

This study compared computational fluid dynamic (CFD) model predictions on aerosol deposition in six asthmatic patients to the in-vivo results of the same group. Patient-specific ventilation and internal air distribution were prescribed using inspiratory and expiratory CT scans of each patient, accounting for individual lobar air flow distribution. Moreover, the significant influence of realistic mouth and throat geometries on regional deposition is demonstrated. The in-vivo data were obtained from single photon emission computed tomography (SPECT) in 6 subjects with mild asthma selected from a database of historical clinical trials. The governing flow and particle tracking equations were solved numerically using a commercial CFD tool, and the modeled deposition results were compared to the SPECT data. Good agreement was found between the CFD model, applying k-ω SST turbulence model, and SPECT in terms of aerosol deposition. The average difference for the lobar deposition obtained from CFD model and SPECT/CT data was 2.1%. The high level of agreement is due to applying patient specific airway geometries and inspiratory/expiratory CT images, anatomical upper airways, and realistic airway trees. The results of this study show that CFD is a powerful tool to simulate patient-specific deposition if correct boundary conditions are applied and can generate similar information obtained with functional imaging tools, such as SPECT., (© 2024. The Author(s).)

Long-COVID patients present with a decline in physical fitness. The aim of this study is to reveal the impact of pulmonary rehabilitation (PR) on physical fitness, quality of life (QoL), and parameters of quantified thorax CT. Long-COVID patients enrolled in a 3-month PR program were retrospectively studied. PR included endurance and resistance training three times a week. Assessments pre- and post-rehabilitation included quantified chest CT, pulmonary function tests (PFT), six-minute walk test (6MWT), cardiopulmonary exercise test, and questionnaires: Hospital Anxiety and Depression Scale, post-COVID-19 Functional Status scale, Borg score, and EuroQol. Seventeen subjects (5M/12F), mean age 42 ± 13 years, were included. PR improved all questionnaires' results significantly. Only significant difference in PFT parameters was correlation between baseline total lung capacity (TLC) and difference in TLC pre- and post-rehabilitation (p = 0.002). 6MWT increased from 329 to 365 m (p < 0.001), VO2max changed from 21 to 24 mL/kg/min (p = 0.007), peak load increased from 116 to 141 Watt (p < 0.001). Blood volume in small pulmonary vessels of 1.25 to 5 mm 2 in cross-sectional area (BV5%) was higher than observed in patients with acute COVID-19 infection. After rehabilitation, BV5% decreased from 65% to 62% (p = 0.020). These changes correlated directly with changes in TLC (p = 0.039). Quantified CT airway volume increased after rehabilitation (p = 0.013). After rehabilitation, TLC tended to normalize due to (re)opening of small airways, with decline in air trapping and recruitment of alveoli. Furthermore, this study revealed that pulmonary rehabilitation can improve QoL and physical fitness in long-COVID patients., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function., Methods: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siV aw ) and resistance (siR aw ) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siV aw and siR aw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siV aw and siR aw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV 1 ) and COPD Assessment Test (CAT) were also assessed., Results: There were no significant changes in pre-dose siV aw or siR aw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siR aw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siV aw and siR aw (siV aw : 39.8% and 62.6%; siR aw : - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siV aw : 77.9%; siR aw : - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV 1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001)., Conclusions: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Patients with post-acute sequelae of COVID-19 (PASC) present with a decrease in physical fitness. The aim of this paper is to reveal the relations between the remaining symptoms, blood volume distribution, exercise tolerance, static and dynamic lung volumes, and overall functioning. Patients with PASC were retrospectively studied. Pulmonary function tests (PFT), 6-minute walk test (6MWT), and cardiopulmonary exercise test were performed. Chest CT was taken and quantified. Patients were divided into two groups: minor functional limitations (MFL) and severe functional limitations (SFL) based on the completed Post-COVID-19 Functional Status scale (PCFS). Twenty one patients (3 M; 18 FM), mean age 44 (IQR 21) were studied. Eighteen completed the PCFS (8 MFL; 10 SFL). VO 2 max was suboptimal in both groups (not significant). 6MWT was significantly higher in MFL-group (p = 0.043). Subjects with SFL, had significant lower TLC (p = 0.029). The MFL-group had more air trapping (p = 0.036). Throughout the sample, air trapping correlated significantly with residual volume (RV) in L (p < 0.001). An increase in air trapping was related to an increase in BV5 (p < 0.001). Mean BV5 was 65% (IQR 5%). BV5% in patients with PASC was higher than in patients with acute COVID-19 infection. This increase in BV5% in patients with PASC is thought to be driven by the air trapping in the lobes. This study reveals that symptoms are more driven by occlusion of the small airways. Patients with more physical complaints have significantly lower TLC. All subjects encounter physical limitations as indicated by suboptimal VO 2 max. Treatment should focus on opening or re-opening of small airways by recruiting alveoli., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Throughout the COVID-19 pandemic, a portion of those affected have evolved toward acute hypoxic respiratory failure. Initially, this was hypothesized to result from acute lung injury leading to acute respiratory distress syndrome (ARDS). In previous research, a novel quantitative CT post-processing technique was described to quantify the volume of blood contained within pulmonary blood vessels of a given size. We hypothesized that patients with lower BV5 blood flow would have higher supplemental oxygen needs and less favorable arterial blood gas profiles. From the initial data analysis, 111 hospitalized COVID-19 patients were retrospectively selected based on the availability of CT scans of the lungs with a slice thickness of 1.5 mm or less, as well as PCR-confirmed SARS-CoV2 infection. Three-dimensional (3-D) reconstructions of the lungs and pulmonary vasculature were created. Further analysis was performed on 50 patients. Patients were divided into groups based on their need for oxygen at the time of CT scan acquisition. Eighteen out of 50 patients needed >2 L/min supplemental oxygen and this group demonstrated a significantly lower median percentage of total blood flow in the BV5 vessels compared with the 32 patients who needed <2 L/min supplemental oxygen (41.61% vs. 46.89%, P = 0.023). Both groups had significantly less blood as a proportion in BV5 vessels compared with healthy volunteers. These data are consistent with the hypothesis that reduced blood volume within small (BV5) pulmonary vessels is associated with higher needs for supplemental oxygen and more severe gas exchange anomalies in COVID-19 infections. NEW & NOTEWORTHY This research provides, by using new imaging analysis on CT imaging, an insight into the pathophysiology of patients with COVID-19 infection. By visualizing and quantifying the blood in small vessels in the lung, we can link these results to the clinical need for oxygen in patients with COVID-19 infection.

Background: Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population., Methods: CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations., Results: 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV 1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV 1  ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV 1  < 70%) when comparing FRI to CF-CT scores., Conclusions: Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research., (© 2021. The Author(s).)

Background: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm 3 ., Methods: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study., Results: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV 1 ] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV 1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF., Conclusions: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD., Trial Registration:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.