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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

Jan De Backer,1 Wim Vos,1 Cedric Van Holsbeke,1 Samir Vinchurkar,1 Rita Claes,2 Paul M Parizel,3 Wilfried De Backer2 1FluidDA nv, Kontich, Belgium; 2Department Respiratory Medicine, University Hospital, Antwerp, Belgium; 3Department Radiology, University Hospital, Antwerp, Belgium Background: Previous studies have demonstrated the potential beneficial effect of N-acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD). However, the required dose and responder phenotype remain unclear. The current study investigated the effect of high-dose NAC on airway geometry, inflammation, and oxidative stress in COPD patients. Novel functional respiratory imaging methods combining multislice computed tomography images and computer-based flow simulations were used with high sensitivity for detecting changes induced by the therapy. Methods: Twelve patients with Global Initiative for Chronic Obstructive Lung Disease stage II COPD were randomized to receive NAC 1800 mg or placebo daily for 3 months and were then crossed over to the alternative treatment for a further 3 months. Results: Significant correlations were found between image-based resistance values and glutathione levels after treatment with NAC (P = 0.011) and glutathione peroxidase at baseline (P = 0.036). Image-based resistance values appeared to be a good predictor for glutathione peroxidase levels after NAC (P = 0.02), changes in glutathione peroxidase levels (P = 0.035), and reduction in lobar functional residual capacity levels (P = 0.00084). In the limited set of responders to NAC therapy, the changes in airway resistance were in the same order as changes induced by budesonide/formoterol. Conclusion: A combination of glutathione, glutathione peroxidase, and imaging parameters could potentially be used to phenotype COPD patients who would benefit from addition of NAC to their current therapy. The findings of this small pilot study need to be confirmed in a larger pivotal trial. Keywords: functional respiratory imaging, computational fluid dynamics, computed tomography, chronic obstructive pulmonary disease, N-acetylcysteine

Kris Ides,1–3 Wim Vos,3,4 Lieve De Backer,2,3 Dirk Vissers,1,2 Rita Claes,2,3 Glenn Leemans,1,2 Kevin Ongena,1 Oswald Peters,5 Wilfried De Backer1–31Department of Health Science, Artesis University College of Antwerp, Merksem, 2Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, 3Department of Respiratory Medicine, Antwerp University Hospital, Edegem, 4FluidDa.nv, Groeningerlei, Kontich, Belgium, 5AZ Monica, Antwerp, BelgiumObjective: Chest physiotherapy enhances sputum evacuation in COPD patients. It can be applied as a single technique or as a combination of techniques including intrapulmonary percussive ventilation (IPV). Recently developed assessment techniques may provide new insights into the effect of airway clearance techniques.Participants: Five moderate to severe COPD patients (three females and two males; mean forced expiratory volume in 1 second of 39.49% predicted) who were admitted in the hospital for an acute exacerbation were included in this study.Methods: A novel imaging technique was used, together with other conventional techniques, to visualize the short-term effects of a single IPV treatment in COPD patients.Results: No significant changes were noted in the lung function parameters or arterial blood gases measured within 1 hour after the end of the IPV session. Computed tomography images detected changes in the airway patency after the IPV treatment compared with before treatment. Local resistances, calculated for the three-dimensional models, showed local changes in airway resistance.Conclusion: The effects of a single IPV session can be visualized by functional imaging. This functional imaging allows a calculation of changes in local airway resistance and local changes in airway volume in COPD patients without affecting conventional lung function parameters.Keywords: IPV, lung function, forced oscillation technique, physical therapy, airway clearance technique

L De Backer¹, W Vos², B Dieriks¹, D Daems¹, S Verhulst¹, S Vinchurkar², K Ides¹, J De Backer², P Germonpre¹, W De Backer¹1Antwerp University Hospital, Department of Respiratory Medicine, 2FluidDa, Antwerp, BelgiumIntroduction: Noninvasive ventilation (NIV) is a well-established treatment for acute-on-chronic respiratory failure in hypercapnic COPD patients. Less is known about the effects of a long-term treatment with NIV in hypercapnic COPD patients and about the factors that may predict response in terms of improved oxygenation and lowered CO2 retention.Methods: In this study, we randomized 15 patients to a routine pharmacological treatment (n = 5, age 66 [standard deviation ± 6] years, FEV1 30.5 [±5.1] %pred, PaO2 65 [±6] mmHg, PaCO2 52.4 [±6.0] mmHg) or to a routine treatment and NIV (using the Synchrony BiPAP device [Respironics, Inc, Murrsville, PA]) (n = 10, age 65 [±7] years, FEV1 29.5 [±9.0] %pred, PaO2 59 [±13] mmHg, PaCO2 55.4 [±7.7] mmHg) for 6 months. We looked at arterial blood gasses, lung function parameters and performed a low-dose computed tomography of the thorax, which was later used for segmentation (providing lobe and airway volumes, iVlobe and iVaw) and post-processing with computer methods (providing airway resistance, iRaw) giving overall a functional image of the separate airways and lobes.Results: In both groups there was a nonsignificant change in FEV1 (NIV group 29.5 [9.0] to 38.5 [14.6] %pred, control group 30.5 [5.1] to 36.8 [8.7] mmHg). PaCO2 dropped significantly only in the NIV group (NIV: 55.4 [7.7] → 44.5 [4.70], P = 0.0076; control: 52.4 [6.0] → 47.6 [8.2], NS). Patients actively treated with NIV developed a more inhomogeneous redistribution of mass flow than control patients. Subsequent analysis indicated that in NIV-treated patients that improve their blood gases, mass flow was also redistributed towards areas with higher vessel density and less emphysema, indicating that flow was redistributed towards areas with better perfusion. There was a highly significant correlation between the % increase in mass flow towards lobes with a blood vessel density of >9% and the increase in PaO2. Improved ventilation–perfusion match and recruitment of previously occluded small airways can explain the improvement in blood gases.Conclusion: We can conclude that in hypercapnic COPD patients treated with long-term NIV over 6 months, a mass flow redistribution occurs, providing a better ventilation–perfusion match and hence better blood gases and lung function. Control patients improve homogeneously in iVaw and iRaw, without improvement in gas exchange since there is no improved ventilation/perfusion ratio or increased alveolar ventilation. These differences in response can be detected through functional imaging, which gives a more detailed report on regional lung volumes and resistances than classical lung function tests do. Possibly only patients with localized small airway disease are good candidates for long-term NIV treatment. To confirm this and to see if better arterial blood gases also lead to better health related quality of life and longer survival, we have to study a larger population.Keywords: noninvasive ventilation, COPD, imaging