Exploring the link between a novel approach for computer aided lung sound analysis and imaging biomarkers: a cross-sectional study.

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

Validation of computational fluid dynamics models for airway deposition with SPECT data of the same population.

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

Personalized pulmonary rehabilitation program for patients with post-acute sequelae of COVID-19: A proof-of-concept retrospective study.

Long-COVID patients present with a decline in physical fitness. The aim of this study is to reveal the impact of pulmonary rehabilitation (PR) on physical fitness, quality of life (QoL), and parameters of quantified thorax CT. Long-COVID patients enrolled in a 3-month PR program were retrospectively studied. PR included endurance and resistance training three times a week. Assessments pre- and post-rehabilitation included quantified chest CT, pulmonary function tests (PFT), six-minute walk test (6MWT), cardiopulmonary exercise test, and questionnaires: Hospital Anxiety and Depression Scale, post-COVID-19 Functional Status scale, Borg score, and EuroQol. Seventeen subjects (5M/12F), mean age 42 ± 13 years, were included. PR improved all questionnaires' results significantly. Only significant difference in PFT parameters was correlation between baseline total lung capacity (TLC) and difference in TLC pre- and post-rehabilitation (p = 0.002). 6MWT increased from 329 to 365 m (p < 0.001), VO2max changed from 21 to 24 mL/kg/min (p = 0.007), peak load increased from 116 to 141 Watt (p < 0.001). Blood volume in small pulmonary vessels of 1.25 to 5 mm2 in cross-sectional area (BV5%) was higher than observed in patients with acute COVID-19 infection. After rehabilitation, BV5% decreased from 65% to 62% (p = 0.020). These changes correlated directly with changes in TLC (p = 0.039). Quantified CT airway volume increased after rehabilitation (p = 0.013). After rehabilitation, TLC tended to normalize due to (re)opening of small airways, with decline in air trapping and recruitment of alveoli. Furthermore, this study revealed that pulmonary rehabilitation can improve QoL and physical fitness in long-COVID patients.

The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN).

BACKGROUND: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. METHODS: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. RESULTS: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001). CONCLUSIONS: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021.

Unraveling pathophysiologic mechanisms contributing to symptoms in patients with post-acute sequelae of COVID-19 (PASC): A retrospective study.

Patients with post-acute sequelae of COVID-19 (PASC) present with a decrease in physical fitness. The aim of this paper is to reveal the relations between the remaining symptoms, blood volume distribution, exercise tolerance, static and dynamic lung volumes, and overall functioning. Patients with PASC were retrospectively studied. Pulmonary function tests (PFT), 6-minute walk test (6MWT), and cardiopulmonary exercise test were performed. Chest CT was taken and quantified. Patients were divided into two groups: minor functional limitations (MFL) and severe functional limitations (SFL) based on the completed Post-COVID-19 Functional Status scale (PCFS). Twenty one patients (3 M; 18 FM), mean age 44 (IQR 21) were studied. Eighteen completed the PCFS (8 MFL; 10 SFL). VO2 max was suboptimal in both groups (not significant). 6MWT was significantly higher in MFL-group (p = 0.043). Subjects with SFL, had significant lower TLC (p = 0.029). The MFL-group had more air trapping (p = 0.036). Throughout the sample, air trapping correlated significantly with residual volume (RV) in L (p < 0.001). An increase in air trapping was related to an increase in BV5 (p < 0.001). Mean BV5 was 65% (IQR 5%). BV5% in patients with PASC was higher than in patients with acute COVID-19 infection. This increase in BV5% in patients with PASC is thought to be driven by the air trapping in the lobes. This study reveals that symptoms are more driven by occlusion of the small airways. Patients with more physical complaints have significantly lower TLC. All subjects encounter physical limitations as indicated by suboptimal VO2 max. Treatment should focus on opening or re-opening of small airways by recruiting alveoli.

The effect of posture on airflow distribution, airway geometry and air velocity in healthy subjects.

BACKGROUND: Gravity, and thus body position, can affect the regional distribution of lung ventilation and blood flow. Therefore, body positioning is a potential tool to improve regional ventilation, thereby possibly enhancing the effect of respiratory physiotherapy interventions. In this proof-of-concept study, functional respiratory imaging (FRI) was used to objectively assess effects of body position on regional airflow distribution in the lungs. METHODS: Five healthy volunteers were recruited. The participants were asked during FRI first to lie in supine position, afterwards in standardized right lateral position. RESULTS: In right lateral position there was significantly more regional ventilation also described as Imaging Airflow Distribution in the right lung than in the left lung (P < 0.001). Air velocity was significantly higher in the left lung (P < 0.05). In right lateral position there was significantly more airflow distribution in the right lung than in the left lung (P < 0.001). Significant changes were observed in airway geometry resulting in a decrease in imaged airway volume (P = 0.024) and a higher imaged airway resistance (P = 0.029) in the dependent lung. In general, the effect of right lateral position caused a significant increase in regional ventilation (P < 0.001) in the dependent lung when compared with the supine position. CONCLUSIONS: Changing body position leads to significant changes in regional lung ventilation, objectively assessed by FRI The volume based on the imaging parameters in the dependent lung is smaller in the lateral position than in the supine position. In right lateral decubitus position, airflow distribution is greater in dependent lung compared to the nondependent lung. TRIAL REGISTRATION: The trial has been submitted to www. CLINICALTRIALS: gov with identification number NCT01893697 on 07/02/2013.

CT-derived measurements of pulmonary blood volume in small vessels and the need for supplemental oxygen in COVID-19 patients.

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

Functional imaging improves patient selection for mandibular advancement device treatment outcome in sleep-disordered breathing: a prospective study.

STUDY OBJECTIVES: Mandibular advancement devices (MADs) are a noninvasive treatment option for patients with obstructive sleep apnea (OSA) and act by increasing the upper airway volume. However, the exact therapeutic mechanism of action remains unclear. The aim of this study was to assess MAD mechanisms using functional imaging that combines imaging techniques and computational fluid dynamics and assess associations with treatment outcome. METHODS: One hundred patients with OSA were prospectively included and treated with a custom-made MAD at a fixed 75% protrusion. A low-dose computed tomography scan was made with and without MADs for computational fluid dynamics analysis. Patients underwent a baseline and 3-month follow-up polysomnography to evaluate treatment efficacy. A reduction in apnea-hypopnea index ≥ 50% defined treatment response. RESULTS: Overall, 71 patients completed both 3-month follow-up polysomnography and low-dose computed tomography scan with computational fluid dynamics analysis. MAD treatment significantly reduced the apnea-hypopnea index (16.5 [10.4-23.6] events/h to 9.1 [3.9-16.4] events/h; P < .001, median [quartile 1-quartile 3]) and significantly increased the total upper airway volume (8.6 [5.4-12.8] cm3 vs 10.7 [6.4-15.4] cm3; P = .003), especially the velopharyngeal volume (2.1 [0.5-4.1] cm3 vs 3.3 [1.8-6.0] cm3; P < .001). However, subanalyses in responders and nonresponders only showed a significant increase in the total upper airway volume in responders, not in nonresponders. CONCLUSIONS: MAD acts by increasing the total upper airway volume, predominantly due to an increase in the velopharyngeal volume. Responders showed a significant increase in the total upper airway volume with MAD treatment, while there was no significant increase in nonresponders. Findings add evidence to implement functional imaging using computational fluid dynamics in routine MAD outcome prediction. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Predicting Therapeutic Outcome of Mandibular Advancement Device Treatment in Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT01532050; Identifier: NCT01532050. CITATION: Van Gaver H, Op de Beeck S, Dieltjens M, et al. Functional imaging improves patient selection for mandibular advancement device treatment outcome in sleep-disordered breathing: a prospective study. J Clin Sleep Med. 2022;18(3):739-750.

The short-term effects of ORKAMBI (lumacaftor/ivacaftor) on regional and distal lung structures using functional respiratory imaging.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has shown modest benefits in previous research, but the exact effects in the cystic fibrosis (CF) lung remain unclear. This study aims to offer novel information on the mode of action of the cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drug by assessing lung structure and function using functional respiratory imaging (FRI). METHODS: CF patients aged ⩾12 years homozygous for F508del were recruited in an open-label study. Before and after 12 weeks of treatment with LUM/IVA, FRI was used to visualize regional information, such as air trapping, lobar volume and airway wall volume. Secondary outcomes included the CF-CT scoring system, spirometry, the Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaire, exercise tolerance and nutritional status. RESULTS: Of the 12 patients enrolled in the study, 11 completed all study visits. Concerning the FRI parameters, hyperinflation of the lung decreased, indicated by a reduction in air trapping and lobar volume at expiration. Also, a decrease in airway wall volume and a redistribution of pulmonary blood volume were noted, which might be related to a decrease in mucus impaction. Airway resistance, airway volume, internal airflow distribution and aerosol deposition pattern did not show significant changes. No significant improvements were found in any of the CF-CT scores or in the spirometric parameters. Other secondary outcomes showed similar results compared with previous research. Correlations at baseline were found between FRI and conventional outcomes, including physical functioning, spirometry and CF-CT scores. CONCLUSIONS: LUM/IVA decreased lung hyperinflation in combination with a potential decrease in mucus impaction, which can be related to an improved mucociliary transport. These results indicate that several FRI parameters, reflecting regional and distal lung structures, are more sensitive to changes caused by LUM/IVA than conventional respiratory outcomes.

Functional respiratory imaging in relation to classical outcome measures in cystic fibrosis: a cross-sectional study.

BACKGROUND: Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population. METHODS: CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations. RESULTS: 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores. CONCLUSIONS: Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.

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.

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/mm3. 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 [FEV1] 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 FEV1 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 ß2-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.

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

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 (FEV1) ≤80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734). Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (-1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was >0% (Pr(θ>0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (-2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%). Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.

Consistent Pulmonary Drug Delivery with Whole Lung Deposition Using the Aerosphere Inhaler: A Review of the Evidence.

Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug-drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The AerosphereTM inhaler, formulated using co-suspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.

Economic Evaluation of Vaccines: Belgian Reflections on the Need for a Broader Perspective.

OBJECTIVES: The standard framework of economic evaluation of health programs, which is increasingly used for policy funding decisions, is insufficiently equipped to reflect the full range of health and economic benefits conferred by vaccines and thus undervalues vaccination. METHODS: In 2019, a group of Belgian health economic and clinical experts, supported by 2 senior international vaccination experts (1 American, 1 Belgian), convened 4 roundtable meetings to highlight which particular value elements of vaccination remain neglected in economic evaluations. RESULTS: They concluded that the standard economic evaluation framework fails to reflect the full value of vaccination with respect to prevention of complications linked to some vaccine-preventable diseases, health gains for caregivers, herd effects, changes in exposure to and distribution of serotypes, the effect on antimicrobial resistance, productivity gains for caregivers and patients, and the distributive implications of vaccination programs. CONCLUSIONS: Here, suggestions are made regarding how these shortcomings can be addressed in future economic evaluations of vaccines and how a more level playing field between vaccines and other health programs can be created.

Interstitial lung disease in systemic sclerosis quantification of disease classification and progression with high-resolution computed tomography: An observational study.

Introduction: Systemic sclerosis-associated interstitial lung disease accounts for up to 20% of mortality in these patients and has a highly variable prognosis. Functional respiratory imaging, a quantitative computed tomography imaging technique which allows mapping of regional information, can provide a detailed view of lung structures. It thereby shows potential to better characterize this disease. Purpose: To evaluate the use of functional respiratory imaging quantitative computed tomography in systemic sclerosis-associated interstitial lung disease staging, as well as the relationship between short-term changes in pulmonary function tests and functional respiratory imaging quantitative computed tomography with respect to disease severity. Materials and methods: An observational cohort of 35 patients with systemic sclerosis was retrospectively studied by comparing serial pulmonary function tests and in- and expiratory high-resolution computed tomography over 1.5-year interval. After classification into moderate to severe lung disease and limited lung disease (using a hybrid method integrating quantitative computed tomography and pulmonary function tests), post hoc analysis was performed using mixed-effects models and estimated marginal means in terms of functional respiratory imaging parameters. Results: At follow-up, relative mean forced vital capacity percentage change was not significantly different in the limited (6.37%; N = 13; p = 0.053) and moderate to severe disease (-3.54%; N = 16; p = 0.102) groups, respectively. Specific airway resistance decreased from baseline for both groups. (Least square mean changes -25.11% predicted (p = 0.006) and -14.02% predicted (p = 0.001) for limited and moderate to severe diseases.) In contrast to limited disease from baseline, specific airway radius increased in moderate to severe disease by 8.57% predicted (p = 0.011) with decline of lower lobe volumes of 2.97% predicted (p = 0.031). Conclusion: Functional respiratory imaging is able to differentiate moderate to severe disease versus limited disease and to detect disease progression in systemic sclerosis.

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

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 mm2 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.

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

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 mm2) 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 mm2 and above 10 mm2, 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.

A Functional Respiratory Imaging Approach to the Effect of an Oscillating Positive Expiratory Pressure Device in Chronic Obstructive Pulmonary Disease.

Purpose: Chronic obstructive pulmonary disease (COPD) patients are prone to suffer from chronic bronchitis, which ultimately affects their quality of life and overall prognosis. Oscillating positive expiratory pressure (oPEP) devices are designed to aid in the mucus clearance by generating positive pressure pulses in the airways. The main aim of this study was to analyze the impact of a specific oPEP device - Aerobika® - on top of standard of care medication in COPD patients' lung dynamics and drug deposition. Patients and Methods: In this single-arm pilot study, patients were assessed using standard spirometry tests and functional respiratory imaging (FRI) before and after a period of 15±3 days of using the oPEP device twice daily (before their standard medication). Results: The utilization of the oPEP device led to a significant increase of 2.88% in specific airway volume after two weeks (1.44 (SE: 0.18) vs 1.48 (SE: 0.19); 95% CI = [0.03%,5.81%]; p=0.048). Moreover, the internal airflow distribution (IAD) was affected by the treatment: patients' changes ranged from -6.74% to 4.51%. Furthermore, IAD changes at the lower lobes were also directly correlated with variations in forced expiratory volume in one second and peak expiratory flow; conversely, IAD changes at the upper lobes were inversely correlated with these clinical parameters. Interestingly, this change in IAD was significantly correlated with changes in lobar drug deposition (r2=0.30, p<0.001). Conclusion: Our results support that the Aerobika device utilization leads to an improved airflow, which in turn causes a shift in IAD and impacts the drug deposition patterns of the concomitant medication in patients with COPD.

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

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 ß2-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% (p = 0.0187) and 23% (p < 0.0001) increases, respectively] and siRaw [25% (p = 0.0219) and 44% (p < 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 versus 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 The reviews of this paper are available via the supplemental material section.

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

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 cmH2O, 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.