Cedric Van Holsbeke

Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature

Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding. Pulmonary veins and systemic vasculature contribute to microvascular disease in CTEPH http://ow.ly/yGK4U

Novel functional imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol.

Background: Inhaled formulations using extrafine particles of long-acting β2-agonists and corticosteroids were developed to optimize asthma treatment. Findings that these combinations reach and treat smaller airways more effectively are predominantly based on general non-specific outcomes with little information on regional characteristics. Objectives: This study aims to assess long-term effects of extrafine beclomethasone/formoterol on small airways of asthmatic patients using novel functional imaging methods. Methods: Twenty-four stable asthma patients were subdivided into three groups (steroid naive, n = 7; partially controlled, n = 6; well controlled, n = 11). Current treatment was switched to a fixed combination of extrafine beclomethasone/formoterol (Foster®; Chiesi Pharmaceuticals, Parma, Italy). Patients underwent lung function evaluation and thorax high-resolution computerized tomography (HRCT) scan. Local airway resistance was obtained from computational fluid dynamics (CFD). Results: After 6 months, the entire population showed improvement in pre-bronchodilation imaging parameters, including small airway volume (p = 0.0007), resistance (p = 0.011), and asthma control score (p = 0.016). Changes in small airway volume correlated with changes in asthma control score (p = 0.004). Forced expiratory volume in 1 s (p = 0.044) and exhaled nitric oxide (p = 0.040) also improved. Functional imaging provided more detail and clinical relevance compared to lung function tests, especially in the well-controlled group where only functional imaging parameters showed significant improvement, while the correlation with asthma control score remained. Conclusions: Extrafine beclomethasone/formoterol results in a significant reduction of small airway obstruction, detectable by functional imaging (HRCT/CFD). Changes in imaging parameters correlated significantly with clinically relevant improvements. This indicates that functional imaging is a useful tool for sensitive assessment of changes in the respiratory system after asthma treatment.

A case series on lung deposition analysis of inhaled medication using functional imaging based computational fluid dynamics in asthmatic patients: effect of upper airway morphology and comparison with in vivo data

Context: Asthma affects 20 million Americans resulting in an economic burden of approximately

The acute effect of budesonide/formoterol in COPD: a multi-slice computed tomography and lung function study

18 billion in the US alone (Allergies and Asthma Foundation 2000; National Center for Environmental Health (NCEH) 1999). Research studies based on differences in patient-specific airway morphology for asthma and the associated effect on deposition of inhaled aerosols are currently not available in the literature. Therefore, the role of morphological variations such as upper airway (extrathoracic) occlusion is not well documented. Objective: Functional imaging based computational fluid dynamics (CFD) of the respiratory airways for five asthmatic subjects is performed in this study using computed tomography (CT) based patient-specific airway models and boundary conditions. Methods: CT scans for 5 asthma patients were used to reconstruct 3D lung models using segmentation software. An averaged inhalation profile and patient-specific lobar flow distribution were used to perform the simulation. The simulations were used to obtain deposition for BDP/Formoterol® HFA pMDI in the patient-specific airway models. Results: The lung deposition obtained using CFD was in excellent agreement with available in vivo data using the same product. Specifically, CFD resulted in 30% lung deposition, whereas in vivo lung deposition was reported to be approximately 31%. Conclusion: It was concluded that a combination of patient-specific airway models and lobar boundary conditions can be used to obtain accurate lung deposition estimates. Lower lung deposition can be expected for patients with higher extrathoracic resistance. Novel respiratory drug delivery devices need to accommodate population sub-groups based on these morphological and anatomical differences in addition to subject age.

The effect of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification of chronic obstructive pulmonary disease (COPD) does not always match with other clinical disease descriptors such as exacerbation frequency and quality of life, indicating that forced expiratory volume in 1 s (FEV1) is not a perfect descriptor of the disease. The aim of this study was to find out whether changes in airway geometry after inhalation of the most commonly used inhalation therapy in severe COPD can more adequately be described with an image-based approach than with spirometry. 10 COPD GOLD stage III patients were assessed in a double-blind crossover study. Airway volumes were analysed using segmentation of multi-slice computed tomography (MSCT) images; airway resistance was determined using computational fluid dynamics (CFD). Distal airway volume significantly increased (p=0.011) in patients 4 h after receiving a budesonide/formoterol combination from 9.6±4.67 cm3 to 10.14±4.81 cm3. Also CFD-determined airway resistance significantly decreased (p=0.047) from 0.051±0.021 kPa·s·L−1 to 0.043±0.019 kPa·s·L−1. None of the lung function parameters showed a significant change. Only functional residual capacity (FRC) showed a trend to decline (p=0.056). Only the image-based parameters were able to predict the visit at which the combination product was administered. This study showed that imaging is a sensitive, complementary tool to describe changes in airway structure.

Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients

To the Editor: Recently, roflumilast has been added as a therapeutic option for chronic obstructive pulmonary disease (COPD). Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor [1]. The main concern of the large-scale studies performed was that they did not assess the effect of roflumilast in addition to a combination product such as long-acting β2-agonists (LABA) or long-acting muscarinic agents (LAMA) combined with inhaled corticosteroids (ICS) [2]. A novel technology called functional respiratory imaging (FRI) defines, in great detail, lung geometry and regional changes in airway volume and resistance [3–5]. By assessing changes close to the site of action of the intervention, the method is more sensitive (higher effect size) compared with standard pulmonary function tests (PFT) [3]. This implies that the mode of action of an intervention can be assessed in a small number of patients, while maintaining sufficient power to have statistically significant results [3, 4]. We performed a study aimed at investigating the mode of action of roflumilast in COPD patients on top of triple therapy (LABA/LAMA/ICS), using PFT, exercise tolerance tests, patient-reported outcomes (PRO) and FRI. The hypothesis was that roflumilast provides a large benefit to a subset of COPD patients and that FRI can assist in phenotyping these responders. Ideally, a PFT parameter could be defined that could identify the responding phenotype. A …

Anatomical and functional changes in the upper airways of sleep apnea patients due to mandibular repositioning: a large scale study.

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

Change in upper airway geometry between upright and supine position during tidal nasal breathing.

The obstructive sleep apnea-hypopnea syndrome (OSAHS) is a sleep related breathing disorder. A popular treatment is the use of a mandibular repositioning appliance (MRA) which advances the mandibula during the sleep and decreases the collapsibility of the upper airway. The success rate of such a device is, however, limited and very variable within a population of patients. Previous studies using computational fluid dynamics have shown that there is a decrease in upper airway resistance in patients who improve clinically due to an MRA. In this article, correlations between patient-specific anatomical and functional parameters are studied to examine how MRA induced biomechanical changes will have an impact on the upper airway resistance. Low-dose computed tomography (CT) scans are made from 143 patients suffering from OSAHS. A baseline scan and a scan after mandibular repositioning (MR) are performed in order to study variations in parameters. It is found that MR using a simulation bite is able to induce resistance changes by changing the pharyngeal lumen. The change in minimal cross-sectional area is the best parameter to predict the change in upper airway resistance. Looking at baseline values, the ideal patients for MR induced resistance decrease seem to be women with short airways, high initial resistance and no baseline occlusion.

The Effects of Extrafine Beclometasone/Formoterol (BDP/F) on Lung Function, Dyspnea, Hyperinflation, and Airway Geometry in COPD Patients: Novel Insight Using Functional Respiratory Imaging

BACKGROUND As the upper airway is the most important limiting factor for the deposition of inhalation medication in the lower airways, it is interesting to assess how its morphology varies between different postures. The goal of this study is to compare the upper airway morphology and functionality of healthy volunteers in the upright and supine positions during tidal nasal breathing and to search for baseline indicators for these changes. This is done by performing three-dimensional measurements on computed tomography (CT) and cone beam computed tomography (CBCT) scans. METHODS This prospective study was approved by all relevant institutional review boards. All patients gave their signed informed consent. In this study, 20 healthy volunteers (mean age, 62 years; age range, 37-78 years; mean body mass index, 29.26; body mass index range, 21.63-42.17; 16 men, 4 women) underwent a supine low-dose CT scan and an upright CBCT scan of the upper airway. The (local) average (Savg) and minimal (Smin) cross-sectional area, the position of the latter, the concavity, and the airway resistance were examined to determine if they changed from the upright to the supine position. If changes were found, baseline parameters were sought that were indicators for these differences. RESULTS There were five dropouts due to movement artifacts in the CBCT scans. Savg and Smin were 9.76% and 26.90% larger, respectively, in the CBCT scan than in the CT scan, whereas the resistance decreased by 26.15% in the upright position. The Savg of the region between the hard palate and the bottom of the uvula increased the most (49.85%). In people with a high body mass index, this value changed the least. The airway resistance in men decreased more than in women. CONCLUSIONS This study demonstrated that there are differences in upper airway morphology and functionality between the supine and upright positions and that there are baseline indicators for these differences.

Patient-Specific Modeling of Regional Antibiotic Concentration Levels in Airways of Patients with Cystic Fibrosis: Are We Dosing High Enough?

BACKGROUND The efficacy of inhaled corticosteroids (ICS) in moderately severe COPD patients remains unclear. At the same time, the use of extrafine particles in COPD patients is a topic of ongoing research. OBJECTIVES This study assessed the effect of ICS in steroid-naïve mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients previously using ICS when switching to an extrafine particle BDP/F formulation (Foster using Modulite technology, Chiesi Pharmaceutici, Parma, Italy). METHODS Novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and Computational Fluid Dynamics, were used in combination with conventional pulmonary function tests and patient reported outcomes. RESULTS The study showed that the administration of extrafine BDP/F after 4-6 h led to a significant improvement in lung function parameters and hyperinflation as determined by spirometry, body plethysmography, and functional respiratory imaging. After 6 months of treatment, it was observed that, compared to baseline, the hyperinflation on lobar level at total lung capacity was significantly reduced (-1.19±7.19 %p, p=0.009). In addition, a significant improvement in SGRQ symptom score was noted in the entire patient population. Patients who improved in terms of hyperinflation also improved their MMRC dyspnea score. CFD indicated a difference in regional deposition between extrafine and non-extrafine formulations with -11% extrathoracic deposition and up to +4% lobe deposition for the extrafine formulation. CONCLUSIONS The study showed that the administration of extrafine BDP/F improved lung function parameters and hyperinflation. Patients previously treated with ICS remained stable despite the lower dose, while ICS naïve patients improved in terms of lobar hyperinflation. FRI seems to be a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry. The next step is to confirm these findings in a controlled trial.