Publications by authors named "Jan De Backer"

46 Publications

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

Respir Res 2021 Jul 1;22(1):191. Epub 2021 Jul 1.

AstraZeneca, Gothenburg, Sweden.

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.

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] 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 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-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.
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http://dx.doi.org/10.1186/s12931-021-01772-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247252PMC
July 2021

Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials.

Int J Chron Obstruct Pulmon Dis 2021 3;16:1621-1636. Epub 2021 Jun 3.

Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.

Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD).

Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD.

Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry.

Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged.

Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.
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http://dx.doi.org/10.2147/COPD.S309303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184158PMC
June 2021

An Inhaled PI3Kδ Inhibitor Improves Recovery in Acutely Exacerbating COPD Patients: A Randomized Trial.

Int J Chron Obstruct Pulmon Dis 2021 3;16:1607-1619. Epub 2021 Jun 3.

Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.

Purpose: 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 (FEV) ≤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 FEV (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 FEV. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.
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http://dx.doi.org/10.2147/COPD.S309129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184151PMC
June 2021

Altered pulmonary blood volume distribution as a biomarker for predicting outcomes in COVID-19 disease.

Eur Respir J 2021 Mar 18. Epub 2021 Mar 18.

Department of Medicine, Banner University Medical Center Phoenix, Phoenix, Arizona, USA.

Background: Evidence suggests that vascular inflammation and thrombosis may be important drivers of poor clinical outcomes in patients with COVID-19. We hypothesized that a significant decrease in the percentage of blood vessels with a cross-sectional area between 1.25-5 mm2 (BV5%) on chest computed tomography (CT) in COVID-19 patients is predictive of adverse clinical outcomes.

Methods: Retrospective analysis of chest CT scans from 10 hospitals across two state in 313 COVID-19 positive and 195 COVID-19 negative patients seeking acute medical care.

Results: BV5% was predictive of outcomes in COVID-19 patients in a multivariate model, with a BV5% threshold below 25% associated with an odds ratio (OR) 5.58 for death, OR 3.20 for intubation, and OR 2.54 for the composite of death or intubation. A model using age and BV5% had an area under the receiver operating characteristic curve 0.85 to predict the composite of intubation or death in COVID-19 patients. BV5% was not predictive of clinical outcomes in patients without COVID-19.

Conclusion: This data suggests BV5% as a novel biomarker for predicting adverse outcomes in patients with COVID-19 seeking acute medical care.
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http://dx.doi.org/10.1183/13993003.04133-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908189PMC
March 2021

Functional respiratory imaging provides novel insights into the long-term respiratory sequelae of bronchopulmonary dysplasia.

Eur Respir J 2021 06 4;57(6). Epub 2021 Jun 4.

Laboratory for Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium.

Rationale: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Lung function and imaging are classically used to assess BPD. Functional respiratory imaging (FRI) combines a structural and functional assessment of the airways and their vasculature. We aimed to assess BPD using FRI and to correlate these findings with the clinical presentation.

Methods: We included 37 adolescents with a history of preterm birth (22 BPD cases and 15 preterm controls). The study protocol included a detailed history, lung function testing and computed tomography (CT) (at total lung capacity (TLC) and functional residual capacity (FRC)) with FRI. CT images were also assessed using the Aukland scoring system.

Results: BPD patients had lower forced expiratory volume in 1 s to forced vital capacity ratio (p=0.02) and impaired diffusion capacity (p=0.02). Aukland CT scores were not different between the two groups. FRI analysis showed higher lobar volumes in BPD patients at FRC (p<0.01), but not at TLC. Airway resistance was significantly higher in the BPD group, especially in the distal airways. Additionally, FRI showed more air trapping in BPD patients, in contrast to findings on conventional CT images.

Conclusion: This study is the first to use FRI in research for BPD. FRI analysis showed higher lobar volumes in BPD patients, indicating air trapping and reduced inspiratory capacity. In contrast to Aukland CT scores, FRI showed more air trapping in the BPD group, suggesting that FRI might be a more sensitive detection method. Importantly, we also showed increased distal airway resistance in BPD patients. By combining structural and functional assessment, FRI may help to better understand the long-term sequelae of BPD.
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http://dx.doi.org/10.1183/13993003.02110-2020DOI Listing
June 2021

Airway Deposition of Extrafine Inhaled Triple Therapy in Patients with COPD: A Model Approach Based on Functional Respiratory Imaging Computer Simulations.

Int J Chron Obstruct Pulmon Dis 2020 7;15:2433-2440. Epub 2020 Oct 7.

Chiesi Farmaceutici, SpA, Parma, Italy.

Introduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs.

Materials And Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients' high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition.

Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively).

Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.
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http://dx.doi.org/10.2147/COPD.S269001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548261PMC
June 2021

Functional respiratory imaging identifies redistribution of pulmonary blood flow in patients with COVID-19.

Thorax 2021 02 28;76(2):182-184. Epub 2020 Aug 28.

Royal Papworth Hospital, Cambridge, UK.

An increasing observation is that some patients with COVID-19 have normal lung compliance but significant hypoxaemia different from typical acute respiratory distress syndrome (ARDS). We hypothesised that changes in pulmonary blood distribution may be partially responsible and used functional respiratory imaging on CT scans to calculate pulmonary blood volume. We found that patients with COVID-19 had significantly reduced blood volume in the smaller calibre blood vessels (here defined as <5 mm cross-sectional area) compared with matched ARDS patients and healthy controls. This suggests that using high levels of PEEP may not alone be enough to oxygenate these patients and that additional management strategies may be needed.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215395DOI Listing
February 2021

Assessment of Small Pulmonary Blood Vessels in COVID-19 Patients Using HRCT.

Acad Radiol 2020 10 25;27(10):1449-1455. Epub 2020 Jul 25.

Department of Respiratory Medicine, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.

Rationale And Objectives: Mounting evidence supports the role of pulmonary hemodynamic alternations in the pathogenesis of COVID-19. Previous studies have demonstrated that changes in pulmonary blood volumes measured on computed tomography (CT) are associated with histopathological markers of pulmonary vascular pruning, suggesting that quantitative CT analysis may eventually be useful in the assessment pulmonary vascular dysfunction more broadly.

Materials And Methods: Building upon previous work, automated quantitative CT measures of small blood vessel volume and pulmonary vascular density were developed. Scans from 103 COVID-19 patients and 107 healthy volunteers were analyzed and their results compared, with comparisons made both on lobar and global levels.

Results: Compared to healthy volunteers, COVID-19 patients showed significant reduction in BV5 (pulmonary blood volume contained in blood vessels of <5 mm) expressed as BV5/(total pulmonary blood volume; p < 0.0001), and significant increases in BV5-10 and BV 10 (pulmonary blood volumes contained in vessels between 5 and 10 mm and above 10 mm, respectively, p < 0.0001). These changes were consistent across lobes.

Conclusion: COVID-19 patients display striking anomalies in the distribution of blood volume within the pulmonary vascular tree, consistent with increased pulmonary vasculature resistance in the pulmonary vessels below the resolution of CT.
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http://dx.doi.org/10.1016/j.acra.2020.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381940PMC
October 2020

Functional respiratory imaging assessment of glycopyrrolate and formoterol fumarate metered dose inhalers formulated using co-suspension delivery technology in patients with COPD.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620916990

AstraZeneca, Morristown, NJ, USA.

Background: Functional respiratory imaging (FRI) is a quantitative postprocessing imaging technique used to assess changes in the respiratory system. Using FRI, we characterized the effects of the long-acting muscarinic antagonist (LAMA), glycopyrrolate metered dose inhaler (GP MDI), and the long-acting β-agonist (LABA), formoterol fumarate metered dose inhaler (FF MDI), on airway volume and resistance in patients with moderate-to-severe chronic obstructive pulmonary disease.

Methods: Patients in this phase IIIb, randomized, double-blind crossover study received twice-daily GP MDI (18 μg) and FF MDI (9.6 μg). Primary endpoints were specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and specific image-based airway resistance (siRaw), measured using FRI. Secondary and other endpoints included additional FRI, spirometry, and body plethysmography parameters. Postdose efficacy assessments were performed within 60-150 min of dosing on day 15.

Results: A total of 23 patients were randomized and 19 completed both treatment periods. GP MDI and FF MDI both achieved significant improvements from baseline to day 15 in siVaw [11% ( = 0.0187) and 23% ( < 0.0001) increases, respectively] and siRaw [25% ( = 0.0219) and 44% ( < 0.0001) reductions, respectively]. Although, on average, improvements were larger for FF MDI than GP MDI, some individuals displayed greater responses with each of the two treatments. These within-patient differences increased with airway generation number. Spirometry and body plethysmography endpoints showed significant improvements from baseline in inspiratory capacity for both treatments, and numeric improvements for other endpoints.

Conclusion: Both GP MDI and FF MDI significantly improved siRaw and siVaw at day 15 baseline. FRI endpoints demonstrated increased sensitivity relative to spirometry and body plethysmography in detecting differences between treatments in a small number of patients. Intra-patient differences in treatment response between the LAMA and the LABA provide further support for the benefit of dual bronchodilator therapies.

Clinicaltrials.gov Registration Number: NCT02937584
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http://dx.doi.org/10.1177/1753466620916990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225799PMC
June 2021

Functional respiratory imaging of the airways in the acute respiratory distress syndrome.

Anaesth Crit Care Pain Med 2020 Apr 7;39(2):207-213. Epub 2020 Feb 7.

Department of Critical Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium.

Background: Alveolar flooding and airway obstruction are present in the acute respiratory distress syndrome. The impact of positive end-expiratory pressure on regional airway aeration has not been described.

Aim: To assess bronchial and lung recruitment and distension during an incremental positive end-expiratory pressure trial in patients with acute respiratory distress syndrome.

Methods: Six patients underwent lung and airway imaging at four positive end-expiratory pressure levels in a cohort trial. Images were post-processed by means of Functional Respiratory Imaging. This technique offers 3-dimensional visualisation and quantification of patients' airway and lung geometry on a regional level.

Results: With increasing positive end-expiratory pressure from 0 to 20 cmHO, the median bronchial recruitment was 151% and the median bronchial distension 43%. Non-aerated lower lobes bronchi had more bronchial volume increase at high positive end-expiratory pressure than partially aerated upper lobes bronchi. Lung recruitment tended to be higher in patients with non-focal acute respiratory distress syndrome. In two patients, bronchial volume increase at high positive end-expiratory pressure largely exceeded bronchial volume increase observed in matched healthy control subjects at total lung capacity, suggesting severe bronchial over-distension.

Conclusions: In early acute respiratory distress syndrome, Functional Respiratory Imaging gives an innovative insight into the relationship between positive end-expiratory pressure-induced bronchial distension and recruitment, positive end-expiratory pressure-induced lung recruitment and hyperinflation and lung morphology.
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http://dx.doi.org/10.1016/j.accpm.2019.10.017DOI Listing
April 2020

Machine Learning Algorithms Utilizing Functional Respiratory Imaging May Predict COPD Exacerbations.

Acad Radiol 2019 09 23;26(9):1191-1199. Epub 2018 Nov 23.

FluidDA nv, Groeningenlei 132, 2550 Kontich, Belgium.

Rationale And Objectives: Acute chronic obstructive pulmonary disease exacerbations (AECOPD) have a significant negative impact on the quality of life and accelerate progression of the disease. Functional respiratory imaging (FRI) has the potential to better characterize this disease. The purpose of this study was to identify FRI parameters specific to AECOPD and assess their ability to predict future AECOPD, by use of machine learning algorithms, enabling a better understanding and quantification of disease manifestation and progression.

Materials And Methods: A multicenter cohort of 62 patients with COPD was analyzed. FRI obtained from baseline high resolution CT data (unenhanced and volume gated), clinical, and pulmonary function test were analyzed and incorporated into machine learning algorithms.

Results: A total of 11 baseline FRI parameters could significantly distinguish ( p < 0.05) the development of AECOPD from a stable period. In contrast, no baseline clinical or pulmonary function test parameters allowed significant classification. Furthermore, using Support Vector Machines, an accuracy of 80.65% and positive predictive value of 82.35% could be obtained by combining baseline FRI features such as total specific image-based airway volume and total specific image-based airway resistance, measured at functional residual capacity. Patients who developed an AECOPD, showed significantly smaller airway volumes and (hence) significantly higher airway resistances at baseline.

Conclusion: This study indicates that FRI is a sensitive tool (PPV 82.35%) for predicting future AECOPD on a patient specific level in contrast to classical clinical parameters.
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http://dx.doi.org/10.1016/j.acra.2018.10.022DOI Listing
September 2019

A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD.

Int J Chron Obstruct Pulmon Dis 2018 30;13:2673-2684. Epub 2018 Aug 30.

AstraZeneca, Gaithersburg, MD, 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 (FEV) 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 <0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV and IC (443 mL and 454 mL, respectively; both <0.001) and reduced FRC and RV (13% and 22%, respectively; both <0.0001). There were no significant safety findings.

Conclusion: GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV, IC, and hyperinflation.

Clinical Trial Registration: ClinicalTrials.gov: NCT02643082.
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http://dx.doi.org/10.2147/COPD.S171707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124470PMC
January 2019

Functional respiratory imaging: heterogeneity of acute exacerbations of COPD.

Int J Chron Obstruct Pulmon Dis 2018 30;13:1783-1792. Epub 2018 May 30.

Department of Pulmonary Diseases, Antwerp University Hospital, Antwerp, Belgium.

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, ≤0.01), airway volume at total lung capacity (+1.70±4.65 L, =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.
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http://dx.doi.org/10.2147/COPD.S152463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985851PMC
January 2019

The Role of Functional Respiratory Imaging in Treatment Selection of Children With Obstructive Sleep Apnea and Down Syndrome.

J Clin Sleep Med 2018 04 15;14(4):651-659. Epub 2018 Apr 15.

Department of Pediatrics, Pediatric Sleep Lab at Antwerp University Hospital, Antwerp, Belgium.

Study Objectives: The complexity of the pathogenesis of obstructive sleep apnea (OSA) in children with Down syndrome (DS) is illustrated by a prevalence of residual OSA after adenotonsillectomy. The aim of this study was to investigate whether upper airway imaging combined with computation fluid dynamics could characterize treatment outcome after adenotonsillectomy in these children.

Methods: Children with DS and OSA were prospectively included. All children underwent an evaluation of the upper airway and an ultra-low dose computed tomography scan of the upper airway before adenotonsillectomy. The upper airway tract was extracted from the scan and combined with computational fluid dynamics. Results were evaluated using control polysomnography after adenotonsillectomy.

Results: Thirty-three children were included: 18 boys, age 4.3 ± 2.3 years, median body mass index z-score 0.6 (-2.9 to 3.0), and median obstructive apnea-hypopnea index was 15.7 (3-70) events/h. The minimal upper airway cross-sectional area was significantly smaller in children with more severe OSA ( = .03). Nineteen children underwent a second polysomnography after adenotonsillectomy. Seventy-nine percent had persistent OSA (obstructive apneahypopnea index > 2 events/h). A greater than 50% decrease in obstructive apnea-hypopnea index was observed in 79% and these children had a significantly higher volume of the regions below the tonsils.

Conclusions: This is the first study to characterize treatment outcome in children with DS and OSA using computed tomography upper airway imaging. At baseline, children with more severe OSA had a smaller upper airway. Children with a less favorable response to adenotonsillectomy had a smaller volume of regions below the tonsils, which could be due to enlargement of the lingual tonsils, glossoptosis, or macroglossia.

Commentary: A commentary on this article appears in this issue on page 501.
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http://dx.doi.org/10.5664/jcsm.7064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886443PMC
April 2018

Changes in ventilation-perfusion during and after an COPD exacerbation: an assessment using fluid dynamic modeling.

Int J Chron Obstruct Pulmon Dis 2018 6;13:833-842. Epub 2018 Mar 6.

Department of Respiratory Medicine, University Hospital Antwerp, Edegem, Belgium.

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 (<0.05).

Conclusion: Recovery of an exacerbation is due to decreased (mainly distal) airway resistance (<0.05). Improvement in patient-reported outcomes were also associated with decreased distal airway resistance (<0.05), but not with forced expiratory volume. FRI is, therefore, a sensitive tool to describe changes in airway caliber, ventilation, and perfusion during and after exacerbation. On the basis of the fact that FRI increased distal airway resistance seems to be the main cause of an exacerbation, therapy should mainly focus on decreasing it during and after the acute event.
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http://dx.doi.org/10.2147/COPD.S153295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846311PMC
September 2018

Use of functional respiratory imaging to characterize the effect of inhalation profile and particle size on lung deposition of inhaled corticosteroid/long-acting β2-agonists delivered via a pressurized metered-dose inhaler.

Ther Adv Respir Dis 2018 Jan-Dec;12:1753466618760948

Mundipharma International Ltd, Cambridge, UK.

Background: Functional respiratory imaging (FRI) uses three-dimensional models of human lungs and computational fluid dynamics to simulate functional changes within airways and predict the deposition of inhaled drugs. This study used FRI to model the effects of different patient inhalation and drug formulation factors on lung deposition of an inhaled corticosteroid/long-acting β-agonist (ICS/LABA) combination, administered by a pressurized metered-dose inhaler.

Methods: Three-dimensional models of the lungs of six patients with asthma (mean forced expiratory volume in 1 s, 83%), treated with an ICS/LABA, were included. FRI modelling was used to simulate (1) the effects on lung deposition of inhalation duration and particle size [fine particle fraction (FPF), proportion of particles <5 µm; and mass median aerodynamic diameter (MMAD), average size of inhalable particles]; (2) deposition of fluticasone propionate/formoterol (FP/FORM) 125/5 µg; and (3) how inhalation profiles and flow rates affected FP/FORM deposition.

Results: Total lung depositions (TLDs) following 1-, 3- and 5-s inhalations were 22.8%, 36.1% and 41.6% (metered dose), respectively, and central-to-peripheral deposition (C:P) ratios were 1.81, 0.86 and 0.61, respectively. TLD increased with increasing FPF, from ~8% at 10% FPF to ~36% at 40% FPF (metered dose); by contrast, MMAD had little effect on TLD, which was similar across MMADs (1.5-4.5 µm) at each FPF. FP/FORM deposited throughout central and peripheral airways with gradual (sinusoidal) and sharp (rapid) inhalations. TLD ranged from 35.8 to 44.0% (metered dose) for gradual and sharp inhalations at 30 and 60 L/min mean flow rates.

Conclusions: These data provide important insights into the potential effects of inhalation characteristics (inhalation profile and duration) and aerosol formulation (FPF) on lung deposition of inhaled therapies. FRI thus represents a useful alternative to scintigraphy techniques. Future FRI studies will further our understanding of the deposition of inhaled drugs and help improve the management of asthma.
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http://dx.doi.org/10.1177/1753466618760948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937159PMC
January 2019

Machine Learning Algorithms Utilizing Quantitative CT Features May Predict Eventual Onset of Bronchiolitis Obliterans Syndrome After Lung Transplantation.

Acad Radiol 2018 09 19;25(9):1201-1212. Epub 2018 Feb 19.

Perelman School of Medicine, University of Pennsylvania, Departments of Radiology and Medicine, 3400 Spruce Street, Philadelphia, PA 19104.

Rationale And Objectives: Long-term survival after lung transplantation (LTx) is limited by bronchiolitis obliterans syndrome (BOS), defined as a sustained decline in forced expiratory volume in the first second (FEV) not explained by other causes. We assessed whether machine learning (ML) utilizing quantitative computed tomography (qCT) metrics can predict eventual development of BOS.

Materials And Methods: Paired inspiratory-expiratory CT scans of 71 patients who underwent LTx were analyzed retrospectively (BOS [n = 41] versus non-BOS [n = 30]), using at least two different time points. The BOS cohort experienced a reduction in FEV of >10% compared to baseline FEV post LTx. Multifactor analysis correlated declining FEV with qCT features linked to acute inflammation or BOS onset. Student t test and ML were applied on baseline qCT features to identify lung transplant patients at baseline that eventually developed BOS.

Results: The FEV decline in the BOS cohort correlated with an increase in the lung volume (P = .027) and in the central airway volume at functional residual capacity (P = .018), not observed in non-BOS patients, whereas the non-BOS cohort experienced a decrease in the central airway volume at total lung capacity with declining FEV (P = .039). Twenty-three baseline qCT parameters could significantly distinguish between non-BOS patients and eventual BOS developers (P < .05), whereas no pulmonary function testing parameters could. Using ML methods (support vector machine), we could identify BOS developers at baseline with an accuracy of 85%, using only three qCT parameters.

Conclusions: ML utilizing qCT could discern distinct mechanisms driving FEV decline in BOS and non-BOS LTx patients and predict eventual onset of BOS. This approach may become useful to optimize management of LTx patients.
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http://dx.doi.org/10.1016/j.acra.2018.01.013DOI Listing
September 2018

Pathophysiological mechanism of long-term noninvasive ventilation in stable hypercapnic patients with COPD using functional respiratory imaging.

Int J Chron Obstruct Pulmon Dis 2017 28;12:2197-2205. Epub 2017 Jul 28.

Department of Respiratory Medicine, University Hospital Antwerp.

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: PaCO significantly improved from 50.03 mmHg at baseline to 44.75 mmHg after 1 month and 43.37 mmHg after 6 months (=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 (=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.
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http://dx.doi.org/10.2147/COPD.S136412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546189PMC
May 2018

Image-based computational fluid dynamics in the lung: virtual reality or new clinical practice?

Wiley Interdiscip Rev Syst Biol Med 2017 11 13;9(6). Epub 2017 Jun 13.

Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.

The development and implementation of personalized medicine is paramount to improving the efficiency and efficacy of patient care. In the respiratory system, function is largely dictated by the choreographed movement of air and blood to the gas exchange surface. The passage of air begins in the upper airways, either via the mouth or nose, and terminates at the alveolar interface, while blood flows from the heart to the alveoli and back again. Computational fluid dynamics (CFD) is a well-established tool for predicting fluid flows and pressure distributions within complex systems. Traditionally CFD has been used to aid in the effective or improved design of a system or device; however, it has become increasingly exploited in biological and medical-based applications further broadening the scope of this computational technique. In this review, we discuss the advancement in application of CFD to the respiratory system and the contributions CFD is currently making toward improving precision medicine. The key areas CFD has been applied to in the pulmonary system are in predicting fluid transport and aerosol distribution within the airways. Here we focus our discussion on fluid flows and in particular on image-based clinically focused CFD in the ventilatory system. We discuss studies spanning from the paranasal sinuses through the conducting airways down to the level of the alveolar airways. The combination of imaging and CFD is enabling improved device design in aerosol transport, improved biomarkers of lung function in clinical trials, and improved predictions and assessment of surgical interventions in the nasal sinuses. WIREs Syst Biol Med 2017, 9:e1392. doi: 10.1002/wsbm.1392 For further resources related to this article, please visit the WIREs website.
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http://dx.doi.org/10.1002/wsbm.1392DOI Listing
November 2017

Predicting the effect of treatment in paediatric OSA by clinical examination and functional respiratory imaging.

Pediatr Pulmonol 2017 06 7;52(6):799-805. Epub 2017 Mar 7.

Department of Paediatrics, Antwerp University Hospital, Edegem, Belgium.

Objective: The aim of this study was to investigate whether functional respiratory imaging (FRI) or clinical examination could predict treatment outcome for obstructive sleep apnea (OSA) in normal-weight, non-syndromic children.

Methods: Normal weight children diagnosed with OSA by polysomnography were prospectively included. All children got a thorough evaluation and an ultra-low dose computed tomography scan of the upper airway (UA). A 3-D reconstruction was built combined with computational fluid dynamics for FRI. Decisions on the need and type of surgery were based upon findings during drug-induced sleep endoscopy. A second polysomnography was performed 3-12 months after surgery.

Results: Ninety-one children were included: 62 boys, 5.0 ± 2.7 years, and BMI z-score of -0.1 ± 1.2. Children with more severe OSA had a smaller volume of the overlap region between the adenoids and tonsils. Nineteen out of 60 patients had persistent OSA (oAHI >2/h). A lower conductance in the UA and a higher tonsil score predicted successful treatment.

Conclusions: A less constricted airway, as characterized by both FRI and a lower tonsil score, was associated with a less favorable response to (adeno) tonsillectomy. Further studies after treatment using FRI and DISE are warranted to further characterize the UA of these subjects.
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http://dx.doi.org/10.1002/ppul.23684DOI Listing
June 2017

Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension.

Int J Chron Obstruct Pulmon Dis 2016 5;11:1533-41. Epub 2016 Jul 5.

Department of Respiratory Medicine, University Hospital Antwerp, Edegem.

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 (Ω(2) 0=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.
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http://dx.doi.org/10.2147/COPD.S106480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940019PMC
August 2017

Efficacy of inhaled medications in asthma and COPD related to disease severity.

Expert Opin Drug Deliv 2016 Dec 30;13(12):1719-1727. Epub 2016 Jun 30.

a Department of Respiratory Medicine , University Hospital Antwerp , Antwerp , Belgium.

Introduction: The administration of medication by inhalation has become the most important route in treating airway diseases. The efficacy of this route depends on several factors like correct inhalation techniques, compliance and the size of the particles. The flow properties and internal flow distribution contribute to the deposition pattern. Areas covered: What has been less well studied is the effect of the internal flow distribution. We know from recent studies that using systemic anti-inflammatory compounds that open up the distal airways redistributes flow internally and enhances the deposition of inhaled particles to the active site of bronchoconstriction or airway inflammation. We discuss this in more detail in this paper, and also make reference to the use of functional respiratory imaging (FRI) that allows for the description of this flow pattern starting from chest CT followed by post processing with segmentation software and the application of fluid dynamics. Expert opinion: The method that was previously validated does show the importance of redistribution of flow in the final clinical results that could be obtained with inhaled medication, especially in more severe obstructive airway diseases. Based on these insights and novel diagnostic tools, patients in end stage respiratory failure would benefit from a personalized approach with inhaled medication.
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http://dx.doi.org/10.1080/17425247.2016.1200555DOI Listing
December 2016

Functional respiratory imaging to assess the interaction between systemic roflumilast and inhaled ICS/LABA/LAMA.

Int J Chron Obstruct Pulmon Dis 2016 4;11:263-71. Epub 2016 Feb 4.

Department of Respiratory Medicine, University Hospital Antwerp, Wilrijkstraat, Edegem, 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<0.001). Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024). Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029).

Conclusion: The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication. The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy. FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease. Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations.
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http://dx.doi.org/10.2147/COPD.S93830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745845PMC
October 2016

Functional respiratory imaging (FRI) for optimizing therapy development and patient care.

Expert Rev Respir Med 2016 Feb;10(2):193-206

a Department of Respiratory Medicine , University Hospital Antwerp , Edegem , Belgium.

Functional imaging techniques offer the possibility of improved visualization of anatomical structures such as; airways, lobe volumes and blood vessels. Computer-based flow simulations with a three-dimensional element add functionality to the images. By providing valuable detailed information about airway geometry, internal airflow distribution and inhalation profile, functional respiratory imaging can be of use routinely in the clinic. Three dimensional visualization allows for highly detailed follow-up in terms of disease progression or in assessing effects of interventions. Here, we explore the usefulness of functional respiratory imaging in different respiratory diseases. In patients with asthma and COPD, functional respiratory imaging has been used for phenotyping these patients, to predict the responder and non-responder phenotype and to evaluate different innovative therapeutic interventions.
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http://dx.doi.org/10.1586/17476348.2016.1136216DOI Listing
February 2016

Comparison of CT-based Lobar Ventilation with 3He MR Imaging Ventilation Measurements.

Radiology 2016 Feb 28;278(2):585-92. Epub 2015 Aug 28.

From the Academic Units of Academic Radiology (B.A.T., A.J.S., F.C.H., H.M., J.C.K., J.P.R., J.M.W.) and Clinical Oncology (B.A.T., R.H.I.), University of Sheffield, C Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, England; Fluidda, Kontich, Belgium (C.V.H., J.D.B., W.V.); Institute for Lung Health, University of Leicester, Leicester, England (R.H., C.E.B.); Novartis, Basel, Switzerland (R.K.); and INSIGNEO Institute of In-silico Medicine, Sheffield, England (A.J.S., J.M.W.).

Purpose: To compare lobar lung ventilation computed from expiratory and inspiratory computed tomographic (CT) data with direct measurements of ventilation at hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging by using same-breath hydrogen 1 ((1)H) MR imaging examinations to coregister the multimodality images.

Materials And Methods: The study was approved by the national research ethics committee, and written patient consent was obtained. Thirty patients with asthma underwent breath-hold CT at total lung capacity and functional residual capacity. (3)He and (1)H MR images were acquired during the same breath hold at a lung volume of functional residual capacity plus 1 L. Lobar segmentations delineated by major fissures on both CT scans were used to calculate the percentage of ventilation per lobe from the change in inspiratory and expiratory lobar volumes. CT-based ventilation was compared with (3)He MR imaging ventilation by using diffeomorphic image registration of (1)H MR imaging to CT, which enabled indirect registration of (3)He MR imaging to CT. Statistical analysis was performed by using the Wilcoxon signed-rank test, Pearson correlation coefficient, and Bland-Altman analysis.

Results: The mean ± standard deviation absolute difference between the CT and (3)He MR imaging percentage of ventilation volume in all lobes was 4.0% (right upper and right middle lobes, 5.4% ± 3.3; right lower lobe, 3.7% ± 3.9; left upper lobe, 2.8% ± 2.7; left lower lobe, 3.9% ± 2.6; Wilcoxon signed-rank test, P < .05). The Pearson correlation coefficient between the two techniques in all lobes was 0.65 (P < .001). Greater percentage of ventilation was seen in the upper lobes with (3)He MR imaging and in the lower lobes with CT. This was confirmed with Bland-Altman analysis, with 95% limits of agreement for right upper and middle lobes, -2.4, 12.7; right lower lobe, -11.7, 4.6; left upper lobe, -4.9, 8.7; and left lower lobe, -9.8, 2.8.

Conclusion: The percentage of regional ventilation per lobe calculated at CT was comparable to a direct measurement of lung ventilation at hyperpolarized (3)He MR imaging. This work provides evidence for the validity of the CT model, and same-breath (1)H MR imaging enables regional interpretation of (3)He ventilation MR imaging on the underlying lung anatomy at thin-section CT.
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http://dx.doi.org/10.1148/radiol.2015142278DOI Listing
February 2016

Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough?

PLoS One 2015 3;10(3):e0118454. Epub 2015 Mar 3.

Department of Pediatric Pulmonology, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Centre, Rotterdam, the Netherlands.

Background: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF.

Methods: In- and expiratory CT-scans of children with CF (5-17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses.

Results: In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations.

Conclusions: CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118454PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348481PMC
January 2016

Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products.

AAPS J 2015 May 26;17(3):758-68. Epub 2015 Feb 26.

Pharmacotherapy and Translational Research and Pediatrics (Pulmonary), University of Florida, PO Box 100486, Gainesville, Florida, 32610-0486, USA,

In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of β-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.
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http://dx.doi.org/10.1208/s12248-015-9735-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406969PMC
May 2015
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