Publications by authors named "Wim Vos"

70 Publications

Radiomics in Lung Diseases Imaging: State-of-the-Art for Clinicians.

J Pers Med 2021 Jun 25;11(7). Epub 2021 Jun 25.

Department of Respiratory Medicine, University Hospital of Liège, 4000 Liège, Belgium.

Artificial intelligence (AI) has increasingly been serving the field of radiology over the last 50 years. As modern medicine is evolving towards precision medicine, offering personalized patient care and treatment, the requirement for robust imaging biomarkers has gradually increased. Radiomics, a specific method generating high-throughput extraction of a tremendous amount of quantitative imaging data using data-characterization algorithms, has shown great potential in individuating imaging biomarkers. Radiomic analysis can be implemented through the following two methods: hand-crafted radiomic features extraction or deep learning algorithm. Its application in lung diseases can be used in clinical decision support systems, regarding its ability to develop descriptive and predictive models in many respiratory pathologies. The aim of this article is to review the recent literature on the topic, and briefly summarize the interest of radiomics in chest Computed Tomography (CT) and its pertinence in the field of pulmonary diseases, from a clinician's perspective.
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http://dx.doi.org/10.3390/jpm11070602DOI Listing
June 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

Deep learning for the fully automated segmentation of the inner ear on MRI.

Sci Rep 2021 Feb 3;11(1):2885. Epub 2021 Feb 3.

The D-Lab, Department of Precision Medicine, GROW-School for Oncology, Maastricht University, Maastricht, The Netherlands.

Segmentation of anatomical structures is valuable in a variety of tasks, including 3D visualization, surgical planning, and quantitative image analysis. Manual segmentation is time-consuming and deals with intra and inter-observer variability. To develop a deep-learning approach for the fully automated segmentation of the inner ear in MRI, a 3D U-net was trained on 944 MRI scans with manually segmented inner ears as reference standard. The model was validated on an independent, multicentric dataset consisting of 177 MRI scans from three different centers. The model was also evaluated on a clinical validation set containing eight MRI scans with severe changes in the morphology of the labyrinth. The 3D U-net model showed precise Dice Similarity Coefficient scores (mean DSC-0.8790) with a high True Positive Rate (91.5%) and low False Discovery Rate and False Negative Rates (14.8% and 8.49% respectively) across images from three different centers. The model proved to perform well with a DSC of 0.8768 on the clinical validation dataset. The proposed auto-segmentation model is equivalent to human readers and is a reliable, consistent, and efficient method for inner ear segmentation, which can be used in a variety of clinical applications such as surgical planning and quantitative image analysis.
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http://dx.doi.org/10.1038/s41598-021-82289-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858625PMC
February 2021

Delta-Like Ligand-Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis.

Cancer Res 2021 Apr 26;81(7):1909-1921. Epub 2021 Jan 26.

Centre for Gynaecological Oncology Amsterdam (CGOA): Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, the Netherlands.

Human papillomavirus (HPV) drives high-grade intraepithelial neoplasia and cancer; for unknown reasons, this occurs most often in the cervical transformation zone. Either mutation or HPV E6-driven inhibition of Notch1 can drive neoplastic development in stratified squamous epithelia. However, the contribution of Notch1 and its Delta-like ligands (DLL) to site susceptibility remains poorly understood. Here, we map DLL1/DLL4 expression in cell populations present in normal cervical biopsies by immunofluorescence. keratinocyte 2D monolayer models, growth assays, and organotypic raft cultures were used to assess the functional role of DLL-Notch signaling in uninfected cells and its modulation by HPV16 in neoplasia. An RNA sequencing-based gene signature was used to suggest the cell of origin of 279 HPV-positive cervical carcinomas from The Cancer Genome Atlas and to relate this to disease prognosis. Finally, the prognostic impact of DLL4 expression was investigated in three independent cervical cancer patient cohorts. Three molecular cervical carcinoma subtypes were identified, with reserve cell tumors the most common and linked to relatively good prognosis. Reserve cells were characterized as DLL1/DLL4, a proliferative phenotype that is temporarily observed during squamous metaplasia and wound healing but appears to be sustained by HPV16 E6 in raft models of low-grade and, more prominently, high-grade neoplasia. High expression of DLL4 was associated with an increased likelihood of cervical cancer-associated death and recurrence. Taken together, DLL4-Notch1 signaling reflects a proliferative cellular state transiently present during physiologic processes but inherent to cervical reserve cells, making them strongly resemble neoplastic tissue even before HPV infection has occurred. SIGNIFICANCE: This study investigates cervical cancer cell-of-origin populations and describes a DLL-Notch1 phenotype that is associated with disease prognosis and that might help identify cells that are susceptible to HPV-induced carcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1996DOI Listing
April 2021

Development and Validation of an Automated Radiomic CT Signature for Detecting COVID-19.

Diagnostics (Basel) 2020 Dec 30;11(1). Epub 2020 Dec 30.

Department of Nuclear Medicine and Oncological Imaging, University Hospital of Liège, 4020 Liège, Belgium.

The coronavirus disease 2019 (COVID-19) outbreak has reached pandemic status. Drastic measures of social distancing are enforced in society and healthcare systems are being pushed to and beyond their limits. To help in the fight against this threat on human health, a fully automated AI framework was developed to extract radiomics features from volumetric chest computed tomography (CT) exams. The detection model was developed on a dataset of 1381 patients (181 COVID-19 patients plus 1200 non COVID control patients). A second, independent dataset of 197 RT-PCR confirmed COVID-19 patients and 500 control patients was used to assess the performance of the model. Diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUC). The model had an AUC of 0.882 (95% CI: 0.851-0.913) in the independent test dataset (641 patients). The optimal decision threshold, considering the cost of false negatives twice as high as the cost of false positives, resulted in an accuracy of 85.18%, a sensitivity of 69.52%, a specificity of 91.63%, a negative predictive value (NPV) of 94.46% and a positive predictive value (PPV) of 59.44%. Benchmarked against RT-PCR confirmed cases of COVID-19, our AI framework can accurately differentiate COVID-19 from routine clinical conditions in a fully automated fashion. Thus, providing rapid accurate diagnosis in patients suspected of COVID-19 infection, facilitating the timely implementation of isolation procedures and early intervention.
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http://dx.doi.org/10.3390/diagnostics11010041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823620PMC
December 2020

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.

Lancet Microbe 2020 Nov 25;1(7):e290-e299. Epub 2020 Sep 25.

Department of Pathology, Amsterdam University Medical Centers (UMC), VU University Amsterdam, Amsterdam, Netherlands.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy.

Methods: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course.

Findings: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78). Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets..

Interpretation: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19.

Funding: Amsterdam UMC Corona Research Fund.
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http://dx.doi.org/10.1016/S2666-5247(20)30144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518879PMC
November 2020

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

A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice.

J Vis Exp 2018 04 13(134). Epub 2018 Apr 13.

Corporate Preclinical R&D, Chiesi Farmaceutici S.p.A.;

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which causes significant deterioration in lung function and subsequent death from respiratory failure. The pathogenesis of IPF in experimental animal models has been induced by bleomycin administration. In this study, we investigate an IPF-like mouse model induced by a double intratracheal bleomycin instillation. Standard histological assessments used for studying lung fibrosis are invasive terminal procedures. The goal of this work is to monitor lung fibrosis through noninvasive imaging techniques such as Fluorescent Molecular Tomography (FMT) and Micro-CT. These two technologies validated with histology findings could represent a revolutionary functional approach for real time non-invasive monitoring of IPF disease severity and progression. The fusion of different approaches represents a step further for understanding the IPF disease, where the molecular events occurring in a pathological condition can be observed with FMT and the subsequent anatomical changes can be monitored by Micro-CT.
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http://dx.doi.org/10.3791/56443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933503PMC
April 2018

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

Anatomic predictors of response and mechanism of action of upper airway stimulation therapy in patients with obstructive sleep apnea.

Sleep 2018 04;41(4)

Antwerp University Hospital and University of Antwerp, Antwerp, Belgium.

Study Objectives: Upper airway stimulation has been shown to be an effective treatment for some patients with obstructive sleep apnea. However, the mechanism by which hypoglossal nerve stimulation increases upper airway caliber is not clear. Therefore, the objective of this study was to identify the mechanism of action of upper airway stimulation. We hypothesized that, with upper airway stimulation, responders would show greater airway opening in the retroglossal (base of the tongue) region, greater hyoid movement toward the mandible, and greater anterior motion in the posterior, inferior region of the tongue compared with nonresponders.

Methods: Seven participants with obstructive sleep apnea who had been successfully treated with upper airway stimulation (responders) and six participants who were not successfully treated (nonresponders) underwent computed tomography imaging during wakefulness with and without hypoglossal nerve stimulation. Responders reduced their apnea-hypopnea index (AHI) by 22.63 ± 6.54 events per hour, whereas nonresponders had no change in their AHI (0.17 ± 14.04 events per hour). We examined differences in upper airway caliber, the volume of the upper airway soft tissue structures, craniofacial relationships, and centroid tongue and soft palate movement between responders and nonresponders with and without hypoglossal nerve stimulation.

Results: Our data indicate that compared with nonresponders, responders had a smaller baseline soft palate volume and, with stimulation, had (1) a greater increase in retroglossal airway size; (2) increased shortening of the mandible-hyoid distance; and (3) greater anterior displacement of the tongue.

Conclusions: These results suggest that smaller soft palate volumes at baseline and greater tongue movement anteriorly with stimulation improve the response to upper airway stimulation.
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http://dx.doi.org/10.1093/sleep/zsy021DOI Listing
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

[Functional respiratory imaging after neostigmine- or sugammadex-enhanced recovery from neuromuscular blockade in the anesthetised rat: a randomised controlled pilot study].

Rev Bras Anestesiol 2017 Sep - Oct;67(5):443-449. Epub 2017 May 16.

University of Antwerp, Deparment of Algology, Wilrijk, Bélgica.

Objectives: Reductions in diaphragm activity are associated with the postoperative development of atelectasis. Neostigmine reversal is also associated with increased atelectasis. We assessed the effects of neostigmine, sugammadex, and spontaneous reversal on regional lung ventilation and airway flow.

Methods: Six Sprague-Dawley rats were paralysed with rocuronium and mechanically ventilated until recovery of the train-of-four ratio to 0.5. We administered neostigmine (0.06mg.kg), sugammadex (15mg.kg), or saline (n=2 per group). Computed tomography scans were obtained during the breathing cycle. Three-dimensional models of lung lobes were generated using functional respiratory imaging technology, and lobar volumes were calculated during the breathing cycle. The diaphragmatic surface was segmented for the end-expiratory and end-inspiratory scans. The total change in volume was reported by the lung volume change from the end-expiratory scan to the end-inspiratory scan. Chest wall movement was defined as the lung volume change minus the volume change that resulted from diaphragm excursion.

Results: The two rats that received neostigmine exhibited a smaller relative contribution of diaphragm movement to the total change in lung volume compared with the two rats that received sugammadex or saline (chest wall contribution (%): 26.69 and 25.55 for neostigmine; -2.77 and 15.98 for sugammadex; 18.82 and 10.30 for saline).

Conclusion: This pilot study in rats demonstrated an increased relative contribution of chest wall expansion after neostigmine compared with sugammadex or saline. This smaller relative contribution of diaphragm movement may be explained by a neostigmine-induced decrease in phrenic nerve activity or by remaining occupied acetylcholine receptors after neostigmine.
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http://dx.doi.org/10.1016/j.bjan.2017.04.003DOI Listing
May 2019

Longitudinal assessment of bleomycin-induced lung fibrosis by Micro-CT correlates with histological evaluation in mice.

Multidiscip Respir Med 2017 10;12. Epub 2017 Apr 10.

Chiesi S.p.A., Pre-Clinical R & D, Parma, Italy.

Background: The intratracheal instillation of bleomycin in mice induces early damage to alveolar epithelial cells and development of inflammation followed by fibrotic tissue changes and represents the most widely used model of pulmonary fibrosis to investigate human IPF. Histopathology is the gold standard for assessing lung fibrosis in rodents, however it precludes repeated and longitudinal measurements of disease progression and does not provide information on spatial and temporal distribution of tissue damage. Here we investigated the use of the Micro-CT technique to allow the evaluation of disease onset and progression at different time-points in the mouse bleomycin model of lung fibrosis. Micro-CT was throughout coupled with histological analysis for the validation of the imaging results.

Methods: In bleomycin-instilled and control mice, airways and lung morphology changes were assessed and reconstructed at baseline, 7, 14 and 21 days post-treatment based on Micro-CT images. Ashcroft score, percentage of collagen content and percentage of alveolar air area were detected on lung slides processed by histology and subsequently compared with Micro-CT parameters.

Results: Extent (%) of fibrosis measured by Micro-CT correlated with Ashcroft score, the percentage of collagen content and the percentage of alveolar air area (  = 0.91; 0.77; 0.94, respectively). Distal airway radius also correlated with the Ashcroft score, the collagen content and alveolar air area percentage (  = 0.89; 0.78; 0.98, respectively).

Conclusions: Micro-CT data were in good agreement with histological read-outs as micro-CT was able to quantify effectively and non-invasively disease progression longitudinally and to reduce the variability and number of animals used to assess the damage. This suggests that this technique is a powerful tool for understanding experimental pulmonary fibrosis and that its use could translate into a more efficient drug discovery process, also helping to fill the gap between preclinical setting and clinical practice.
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http://dx.doi.org/10.1186/s40248-017-0089-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387277PMC
April 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

Functional respiratory imaging, regional strain, and expiratory time constants at three levels of positive end expiratory pressure in an ex vivo pig model.

Physiol Rep 2016 12;4(23)

School of Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada.

Heterogeneity in regional end expiratory lung volume (EELV) may lead to variations in regional strain (ε). High ε levels have been associated with ventilator-associated lung injury (VALI). While both whole lung and regional EELV may be affected by changes in positive end-expiratory pressure (PEEP), regional variations are not revealed by conventional respiratory system measurements. Differential rates of deflation of adjacent lung units due to regional variation in expiratory time constants (τ) may create localized regions of ε that are significantly greater than implied by whole lung measures. We used functional respiratory imaging (FRI) in an ex vivo porcine lung model to: (i) demonstrate that computed tomography (CT)-based imaging studies can be used to assess global and regional values of ε and τ and, (ii) demonstrate that the manipulation of PEEP will cause measurable changes in total and regional ε and τ values. Our study provides three insights into lung mechanics. First, image-based measurements reveal egional variation that cannot be detected by traditional methods such as spirometry. Second, the manipulation of PEEP causes global and regional changes in R, E, ε and τ values. Finally, regional ε and τ were correlated in several lobes, suggesting the possibility that regional τ could be used as a surrogate marker for regional ε.
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http://dx.doi.org/10.14814/phy2.13059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357821PMC
December 2016

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

Dynamic flow characteristics in normal and asthmatic lungs.

Int J Numer Method Biomed Eng 2015 Dec 25;31(12). Epub 2015 Jun 25.

Department of Computer Science, University of Oxford, Oxford, UK.

Complex flow patterns exist within the asymmetric branching airway network in the lungs. These flow patterns are known to become increasingly heterogeneous during disease as a result of various mechanisms such as bronchoconstriction or alterations in lung tissue compliance. Here, we present a coupled model of tissue deformation and network airflow enabling predictions of dynamic flow properties, including temporal flow rate, pressure distribution, and the occurrence of reverse flows. We created two patient-specific airway geometries, one for a healthy subject and one for a severe asthmatic subject, derived using a combination of high-resolution CT data and a volume-filling branching algorithm. In addition, we created virtually constricted airway geometry by reducing the airway radii of the healthy subject model. The flow model was applied to these three different geometries to solve the pressure and flow distribution over a breathing cycle. The differences in wave phase of the flows in parallel airways induced by asymmetric airway geometry and bidirectional interaction between intra-acinar and airway network pressures were small in central airways but were more evident in peripheral airways. The asthmatic model showed elevated ventilation heterogeneity and significant flow disturbance. The reverse flows in the asthmatic model not only altered the local flow characteristics but also affected total lung resistance. The clinical significance of temporal flow disturbance on lung ventilation in normal airway model is obscure. However, increased flow disturbance and ventilation heterogeneity observed in the asthmatic model suggests that reverse flow may be an important factor for asthmatic lung function.
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http://dx.doi.org/10.1002/cnm.2730DOI Listing
December 2015