Expert Review of Respiratory Medicine
ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20
Functional respiratory imaging (FRI) for optimizing therapy development and patient care Bita Hajian MD, Jan De Backer PhD, Wim Vos PhD, Cedric Van Holsbeke PhD, Johan Clukers MD & Wilfried De Backer MD, PhD To cite this article: Bita Hajian MD, Jan De Backer PhD, Wim Vos PhD, Cedric Van Holsbeke PhD, Johan Clukers MD & Wilfried De Backer MD, PhD (2016): Functional respiratory imaging (FRI) for optimizing therapy development and patient care, Expert Review of Respiratory Medicine, DOI: 10.1586/17476348.2016.1136216 To link to this article: http://dx.doi.org/10.1586/17476348.2016.1136216
Accepted author version posted online: 05 Jan 2016.
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Date: 26 January 2016, At: 02:44
Publisher: Taylor & Francis Journal: Expert Review of Respiratory Medicine DOI: 10.1586/17476348.2016.1136216
Functional respiratory imaging (FRI) for optimizing therapy development and patient care Review
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Bita Hajian, MD1; Jan De Backer, PhD2; Wim Vos, PhD2; Cedric Van Holsbeke, PhD2; Johan Clukers, MD1;Wilfried De Backer, MD, PhD1
1
University Hospital Antwerp, Department of Respiratory Medicine, Belgium
2
FLUIDDA nv, Belgium
Corresponding author: Bita Hajian Wilrijkstraat 10 2650 Edegem Belgium Tel: Email: [email protected] Abstract: 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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KEYWORDS: COPD FRI, phenotype, personalized treatment INTRODUCTION Large-scale clinical studies using a number of inhalation compounds and fixed combination products have been performed with spirometric values as the primary endpoints, primarily including the forced expiratory volume in 1 second (FEV1), as well as the Saint George Respiratory Questionnaire (SGRQ). The FEV1 is still considered the gold standard for the functional assessment of airway diseases both in clinical settings and in pharmacological research. The FEV1 is a dynamic lung volume obtained one second after the start of a forced expiration. The SGRQ questionnaire is a standardized self-completed questionnaire for measuring impaired health and perceived wellbeing ('quality of life') in airway disease. It was been designed to allow comparative measurements of health between patient populations and to quantify changes in health following therapy (1). Many clinical studies (2) indicate changes in respiratory parameters after the administration of the investigated product; however, the clinical significance of these changes is not clear, and the measured parameters are occasionally below the lower limit of reported clinical significance (3). For example, although an overall maximum change in FEV1 of 150 ml was observed, the clinical implication of this value remains uncertain. In addition, regarding the outcome of the SGRQ, the studies often only demonstrate a maximum change of approximately 4, which is recognized as the lower limit for clinical significance; there is typically a weak correlation between SGRQ and FEV1 (4).
In contrast, the prevalence and mortality of respiratory diseases are increasing, with more than 500 million estimated patients. Thus, an unmet need for additional sensitive outcome parameters exists, beginning with outcome parameters that would assist in understanding the mode of action and subsequent pharmacodynamic effect. In this review, we discuss the application of functional respiratory imaging (FRI) to obtain a better understanding of the pathophysiology of respiratory diseases and to optimize therapy development and patient care. FUNCTIONAL RESPIRATORY IMAGING (FRI) AS A BIOMARKER In recent years, imaging of the thorax has evolved substantially from an experimental tool that was used in only a limited number of centers towards becoming a routine test for clinical assessment of the respiratory system. In particular, the development of computed tomography (CT) has greatly increased the understanding of the pathophysiology of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). The imaging method itself has been increasingly used in clinical trials, although the absolute number of studies remains limited. Without additional post processing, a CT scan is limited to static information about the respiratory system. This in itself is already very valuable because, due to the high resolution of CT, certain pathologies (e.g., fibrosis and bronchiectasies) can be distinguished very well.
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Today, CT is the method of choice to determine the extent of emphysema in COPD patients by measuring lung density. Recent developments in the field of flow and structural simulations have made it possible to simulate the behavior of airway flow in a patient in a specific fashion based on the CT images using a method called computational fluid dynamics (CFD). It could therefore be hypothesized that functional parameters derived from patient-specific simulations, such as the modeled airway resistance, can function as a biomarker. Changes in this biomarker could be a reflection of changes that are clinically relevant and are even more sensitive to changes than classical lung function measurements are. FRI also provides regional information and allows for measurable changes at the level of the lobes and airways. In addition, there is the possibility of describing particles in the airflow and airway as well as the lung deposition of the inhaled compounds. Because patients only underwent CT scanning, the procedure is minimally invasive and almost without risk. Radiation exposure nevertheless is a risk, but scan protocols with limited radiation exposure are possible. A typical radiation dose consists of 1-2 mSv per scan (6). This means that the radiation dose is 3 times less than a “classical” CT, which usually has a dose of 10-12 mSv. Because of the low radiation dose, repeated scans in clinical follow-up or in clinical studies can be performed without increasing the radiation dose above the exposure that is currently used for routine examinations. It can be expected that further developments in CT scanners will reduce the radiation even further (7). Using a lower dose can increase the level of noise in the scan. However, this can be mitigated by using appropriate filters and iterative reconstruction algorithms. In addition, the natural contrast between the air and the surrounding tissue allows for a significant reduction in the dose while maintaining the image quality. The radiation dose of CT scans in clinical practice has also been decreased due to these technological innovations. Thus, we believe that the quantification of CT scans through methods such as Functional Respiratory Imaging can become routine for specific applications in a patient population suffering from lung diseases. FRI is essentially a composite biomarker because it includes data concerning lobar volumes, airway volumes, airway resistance and aerosol deposition. With increasing experience with the method, it will become clear what the minimal significant clinical difference for the subsets of parameters will be. For drug development, it can already be used to understand the mode of action, whereas in clinical settings, information about regional airflow distribution and related lung structure and vascularization is obtainable. This is of utmost importance to understand ventilation-perfusion ratios and the effect of interventions or spontaneous fluctuations in this parameter over time.
MEASUREMENT METHODOLOGY OF FRI Functional Respiratory Imaging is a proprietary workflow that was developed and validated by FLUIDDA. The FRI workflow is a combination of several software components and is provided by the company as a service.
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CT scans are taken as mentioned before using a dose reduction protocol (120 kV, 10–100 mAs; noise factor 28; collimation 0.625 mm; rotation time 0.6 sec and pitch factor 1.375) resulting in an effective dose of 1-2 mSv per CT scan. The scan resolution is 0.5 mm3, and the slice increment is 0.6 mm. Scans are taken at two different levels: functional residual capacity (FRC) and total lung capacity (TLC) (Fig 1.). To ensure the correct lung volume, CT scans are respiratory volume gated during the moment of scanning using a pneumotach flow signal.
Figure 1. Signal from respiratory gating to ensure adequate total lung capacity (TLC) and functional residual capacity (FRC) levels to reduce clinical variability.
Subsequently, CT images are segmented using a segmentation program that has been cleared by the FDA’s Center for Devices and Radiological Health (CDRH) under the 510(k) process (Food and Drug Administration, K073468) and has been CE marked in Europe (Conformité Européenne certificate, BE 05/1191.CE.01). This program converts CT images into patient-specific reconstructions of the lung lobes and the airway tree. By segmenting lung lobes at the FRC and TLC, the internal airflow distribution can be derived from the relative volume change. The airway tree is normally evaluated at the TLC level because doing so eliminates the effects of breathing level. At the TLC, the airway structure can be segmented down to the bronchi, with a diameter of approximately 1-2 mm. Beyond this point, the CT resolution is insufficient to distinguish alveolar and intraluminal air. A typical airway model includes 5-10 generations that depend primarily on the disease state of the individual patient. Distal airway volumes (iVaw) can be assessed at individual airways or in different regions.
The smoothed airway reconstructions are subsequently trimmed at the trachea and the terminal bronchi to obtain a model that is suitable for flow simulation. Next, these segmentations are exported to a meshing software package, where they are divided into discrete tetrahedral elements. Flow properties are obtained throughout the flow domain by means of computational fluid dynamics (CFD). The outflow to each lobe is adjusted iteratively for each patient to match the internal flow rate distribution obtained from the CT scans (6,7,8). Measures of resistance (iRaw) in individual airways or different regions corresponding to the volume measurements are obtained from CFD calculations. Resistance is defined as the total pressure drop over an airway divided by the flow rate through that airway. In a typical clinical trial, the imaging procedure will be performed at baseline and after the intervention. Subsequently, the resulting models are overlaid and compared to one another to establish the changes induced by the therapy. APPLICATION OF FRI IN CLINICAL TRIALS
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Virtually all therapies for lung diseases are aimed at changing lung geometry. Bronchodilators and anti-inflammatory compounds are developed to increase the airway lumen. The former does this through smooth muscle relaxation, and the latter does so through inhibition of inflammation. The resulting improvement in lung geometry is a consequence of ameliorated lung function. Patients should breathe better if the therapy is successful. Eventually, breathing better should result in an improved quality of life (QOL). Today, quality of life is assessed using questionnaires or patient-reported outcome parameters (PRO); lung function is usually analyzed via spirometry and body plethysmography. The geometry can be evaluated using imaging modalities such as computed tomography (CT) and functional respiratory imaging (FRI). When considering the three categories (geometry, lung function and QOL), the inherent number of confounding factors increases from geometry over lung function to QOL (Figure 2). For instance, the conventional pulmonary function tests, such as spirometry, measure not only the characteristics of the tracheobronchial tree (lower airways, where the intervention is designed to act) but also the extrathoracic airway (upper airway) characteristics, the muscle force and the patient’s effort. The questionnaires inherently include the effects of comorbidities and depend on the patient’s concentration and willingness to cooperate. With an increased level of confounding factors, the variability of the measured outcome parameter increases, leading to a larger required sample size of the clinical trials. The correlations between the different categories, although significant (p < 0.05), are often weak (low R) due to the large variability in the outcome measure, as described in the next section. By providing information closer to the site of action, imaging and FRI should be able to provide higher signal-to-noise outcome parameters. FRI focuses on the region of interest and the site of action (usually the tracheobronchial region) and thereby eliminates the noise and variability induced by upper airway resistance and compliance, muscle force and patient effort. Thus, by using FRI outcome parameters, the same statistical significance can be achieved with fewer patients. This in turn makes it possible to use clinical trials as a design tool and not as a mere assessment tool. This offers a rationale for using FRI in clinical studies but also in daily praxis, especially in difficult cases where regional information might be helpful in choosing the most adequate treatment approach. In our clinic, we use FRI routinely in patients with COPD gold C and gold D, in patients with diaphragm paralysis and before lung transplantation. We now overview a number of clinical trials in which FRI has been used successfully to elucidate the mode of action or the intervention effect with a higher sensitivity. FRI involves the visualization of anatomical structures, such as airways, lobe volumes and blood vessels, in 3D and adds functionality to these images by means of computer-based flow simulations. Its advantage over the conventional imaging approach, where a radiologist describes the findings, is that FRI quantifies the anatomical structures. In other words, the 3D visualization is expressed in numbers (e.g., airway volume, blood vessel volume) that allow for a highly detailed follow up in terms of disease progression or assessing the effects of interventions. The flow simulations use so much patient-specific information (e.g., airway geometry, internal airflow distribution, inhalation profile) that they provide an accurate idea of the regional resistance and deposition patterns. These parameters cannot be obtained using conventional imaging approaches. The additional benefit of FRI compared to conventional pulmonary functional testing is described in Table 1. Both asthma and COPD patients were studied. Both bronchodilators and antiinflammatory compounds were studied and in both conditions. The rationale for each study is explained, and the main results are summarized.
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Figure 2. Cascading effect of lung interventions (from changes in geometry to better lung function and quality of life) and the associated confounding factors and required sample size.
Studies in asthma using bronchodilators The first study looked at the acute effect of a LABA in asthmatic patients (8). In that study, 14 mild to moderate asthmatic patients were studied. Ten patients in the active group underwent HRCT before and 4 h after the inhalation of a novel long-acting beta (2) agonist (LABA) that acts shortly after inhalation. Four patients in the placebo group were studied for chronic effects and underwent CT scans twice after adequate washout of bronchodilators. In the active group, a significantly increased bronchodilator response was seen with a forced expiratory volume in 1 s (FEV1) of 8.78 +/- 6.27% predicted vs. -3.38 +/- 6.87% predicted in the control group. The changes in FEV1 correlated significantly with the changes in the distal airway volume (r = 0.69, p = 0.007), total airway resistance (r = -0.73, p = 0.003) and distal airway resistance (r = -0.76, p = 0.002), as calculated using the CFD method. The changes in distal R (aw) were not fully homogeneous. In some patients with normal FEV1 at baseline, CFD-based changes in R (aw) were still detectable. Interestingly, although FEV1 correlated well with the changes in geometry, the latter were far more pronounced than the changes in FEV1. This provided an initial confirmation that FEV1 can underestimate the real geometrical changes. In Figure 3, the color code indicates the changes in airway caliber after LABA as well as the changes in airway resistance. It can be seen that the changes do not occur homogeneously. There is both central and peripheral bronchodilation. The differences in sensitivity can also be seen in Figure 4, where the changes in FEV1/FVC are much smaller than those in the imaged airway volumes and resistances.
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Figure 3. Illustration of the changes in volume (%) and resistance (%) post bronchodilation for a chronically treated patient. (Ref 8: Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation, J Biomech 2008)
Figure 4. Significant correlation between the tiffeneau ratio (%) and change in distal volume (%) post bronchodilation (Ref 8: Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation, J Biomech 2008)
Studies in asthma using fixed combinations of ICS-LABA To gain insight into the mode of action of extrafine beclomethasone/formoterol (BDP/F) in small airways of asthmatic patients using functional imaging (9), 24 stable asthmatic patients were subdivided into three groups (steroid naive, n = 7; partially controlled, n = 6; well controlled, n = 11). All patients were switched from their current treatment to a fixed combination of an extrafine HFA solution of BDP/F. Lung function and HRCT of the thorax were performed at inclusion and after 6 months of treatment with the study medication. A steady normal inspiratory flow of 25 l/min was simulated for all patients to mimic the flow properties at tidal breathing. The outflow to each lobe was adjusted iteratively for each patient to match the internal flow rate distribution obtained from the HRCT scans. There was a significant improvement in asthma control with an increase in the ACT score and in the pre-bronchodilation imaging parameters, including small airway volume (p = 0.0007) and
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resistance (p = 0.011). Changes in the asthma control score (ACT) were correlated with changes in small airway volume (p = 0.004). Exhaled nitric oxide (p = 0.040) and forced expiratory volume in 1 s (p = 0.044) also improved. Compared to lung function tests, functional imaging provided more detail and clinical relevance, especially in the wellcontrolled group, where only the functional imaging parameters showed significant improvement; the correlation with the asthma control score remained. BDP/F extrafine formulation can target areas of the lungs that were left untreated by larger-particle fixed combinations, resulting in a significant reduction of small airway obstruction that was detectable by functional imaging (HRCT/CFD). Compared with FEV1, imaging parameters are much more sensitive to detect changes in larger and smaller airways. Functional imaging is a useful tool for the sensitive assessment of changes in the respiratory system after asthma treatment (Figs 5, 6).
Figure 5. Three-dimensional reconstruction of airway structure from HRCT images showing central (gray) and distal (red) airways. (Ref 9: Novel functional imaging of changes in the small airways of patients treated with extrafine beclomethasone/formoterol, Respiration 2013)
Figure 6. Correlation between changes in image-based airway volume (iVaw) and the change in asthma symptom score (ACT) for well-controlled patients. (Ref 9: Novel functional imaging of changes in the small airways of patients treated with extrafine beclomethasone/formoterol, Respiration 2013)
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Studies in COPD using bronchodilators With functional imaging, it is possible to compare the bronchodilating effects of salbutamol and ipratropium bromide in the central and distal airways in patients with chronic obstructive pulmonary disease (COPD). To show this, five patients with Global Initiative for Chronic Obstructive Lung Disease Stage III COPD were randomized to a single dose of salbutamol or ipratropium bromide in a crossover manner, with a 1-week interval between treatments (10). Lung function and a multislice computed tomography scan of the thorax was performed before and two hours after dosing. Central but primarily distal airway dimensions (third to seventh bifurcation) increased significantly after an inhaled beta2agonist (salbutamol) and anticholinergic agent (ipratropium bromide) in patients with severe COPD. The changes observed upon lung function testing were, overall, less pronounced than the changes in airway caliber seen by the imaging method. Salbutamol and ipratropium bromide were equally effective at first glance when looking at lung function tests, but when viewed in more detail with functional imaging, hyporesponsiveness could be shown for salbutamol in one patient. Salbutamol was more effective in the other patients. This pilot study showed that the new techniques of functional imaging and computational fluid dynamics give innovative insight into the modes of action of salbutamol and ipratropium bromide in patients with COPD.
Studies in COPD using fixed combinations of ICS-LABA As with asthmatic patients, functional respiratory imaging was used. This study (11) looked at the effect of ICS in steroid-naïve mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients who had previously used ICS when switching to an extrafine particle beclomethasone/formoterol. Conventional pulmonary function tests, patient-reported outcomes and novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and computational fluid dynamics, were used. The study showed that the administration of extrafine beclomethasone/formoterol after 46 hours 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 at the lobar level in total lung capacity was significantly reduced (-1.19±7.19%p, p=0.009). A significant improvement in the SGRQ symptom score was noted in the entire patient population. A decrease in hyperinflation was compatible with improvement in the MMRC dyspnea score. Comparing FRI before and after treatment, there was a significant difference in regional deposition between extrafine and nonextrafine formulations, with -11% extrathoracic deposition and up to +4% lobe deposition for the extrafine formulation. FRI is a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry (11,12, Table 1). Airway and lobe volumes are direct measurements from the CT data that are obtained through segmentation, whereas the CFD method is used to
determine airway resistance and aerosol deposition characteristics. Having the opportunity to assess parameters on a lobar scale is a significant improvement over the existing techniques, such as spirometry and body plethysmography, which typically use a black box approach.
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Studies on COPD using N-Acetyl Cysteine There is also increasing evidence that oxidative stress in COPD patients will lead to the production of proinflammatory cytokines and growth factors. The transmigration of neutrophils into the lung tissues and abnormal activation are responsible for the overproduction of reactive oxygen species and the release of proteolytic enzymes in the lungs. It is interesting to understand the role of inflammatory compounds and which patients respond to them. A total of 12 COPD GOLD II patients were included (13). Patients were randomized to receive a daily dose of 1800 mg of NAC (N-acetyl cysteine) or placebo for three months, after which they were crossed over to the other arm for another 3-month treatment period. Significant correlations were found between the image-based resistance values and glutathione (GSH) (p=0.011) and glutathione peroxidase (GPx) (p=0.017). Imagebased resistance values appeared to be a good predictor for GSH levels after NAC treatment (p=0.02), changes in the GPx level (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 on the same order as the changes induced by budesonide/formoterol. A combination of GSH, GPx and imaging parameters could potentially be used to phenotype patients who would benefit from the addition of NAC to their current therapy. It appears that patients with low GPx levels at baseline have room for improvement when using anti-oxidant therapy, and these patients appear to be the responders when N-acetyl cysteine is administered. Again, it is important to identify the responder phenotype. The findings of this small pilot study need to be confirmed in a larger pivotal trial.
Studies in COPD using Roflumilast Roflumilast has been added as a therapeutic option for severe COPD patients. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor. The current study aims to assess the mode of action of Roflumilast as an add-on to LABA/LAMA/ICS therapy in severe COPD patients. Forty-one patients were randomized to receive Roflumilast or placebo (14). At baseline and after 6 months of treatment, pulmonary function tests, exercise tolerance tests and functional respiratory imaging (FRI) were performed, and patient-reported outcomes (PRO) were measured. A significant improvement in FEV1 of 66±120 ml (p=0.01) was observed in the Roflumilast group compared to baseline. In the placebo group, the FEV1 declined by -59±71 ml. The response was driven by a subset (n=8) of responders with a change in FEV1 that exceeded its measurement error of 120 ml. The responders experienced worse dynamic hyperinflation during exercise at baseline than did the non-responders. FRI parameters indicated regional changes in hyperinflation after treatment with Roflumilast that led to an improvement in PFT, PRO and exercise tolerance. The anti-inflammatory characteristics of Roflumilast seem to reduce inflammation in the smaller airways, which leads to a reduction in hyperinflation and a change in internal airflow distribution (IAD). The change in IAD enhances the deposition of the LABA/LAMA/ICS therapy and leads to clinical improvements. Patients who suffer from dynamic hyperinflation tend to benefit from Roflumilast. These findings need to be confirmed in larger clinical trials.
The study suggests that patients who are prone to dynamic hyperinflation are the responder phenotype, suggesting that Roflumilast reduces inflammation and, hence, hyperinflation in smaller airways.
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Studies in COPD using NIV Less is known about the noninvasive ventilation (NIV) effects of a long-term treatment in hypercapnic COPD and how these factors may predict a response in terms of improved oxygenation and lowered CO2 retention. Patients actively treated with NIV developed a more inhomogeneous redistribution of mass flow than did control patients. Subsequent analysis indicated that in NIV-treated patients who improved their blood gases, mass flow was also redistributed towards areas with higher vessel density and less emphysema, indicating that flow was redistributed towards areas with better perfusion. A significant correlation has been found between the percentage increase in mass flow towards lobes with a blood vessel density of >9% and the increase in PaO2. The improved ventilation–perfusion match and recruitment of previously occluded small airways can explain the improvement in blood gases. In hypercapnic COPD patients treated with long-term NIV over 6 months, a mass flow redistribution occurs (Fig 7), providing a better ventilation–perfusion match. Control patients improved homogeneously in airway volumes and local airway resistance, without improvement in gas exchange, because there was no improved ventilation/perfusion ratio or increased alveolar ventilation. These differences in response can be detected through functional imaging, which gives a more detailed report on regional lung volumes and resistances than classical lung function tests do. It is possible that only patients with localized small airway disease are good candidates for long-term NIV treatment. To confirm this and determine whether better arterial blood gases also lead to better health related quality of life and longer survival, a larger population must be studied. This study (15) generated the hypothesis that COPD patients benefit from NIV treatment (i.e., are responders) if the treatment redirects incoming air to better-perfused areas. If the NIV treatment does not change the internal airflow distribution or more air is going to areas with less perfusion, then the patient tends to be a non-responder. Internal airflow distribution is based on lobe expansion from expiration to inspiration and can be expressed on a lobar or segmental level
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Figure 7. Mass flow (re)distribution in a patient treated with noninvasive ventilation for 6 months. (Ref 15. The effects of longterm noninvasive ventilation in hypercapnic COPD patients: a randomized controlled pilot study. Int J Chron Obstruct Pulmon Dis 2011)
Studies in COPD using airway clearance techniques A review (16) of the use of different airway clearance techniques (ACT) and their effects in patients with COPD showed that studies that provide solid evidence of the effectiveness of different airway clearance techniques in patients with COPD are rather scarce. A total of 26 articles were included. There is evidence that active breathing techniques, such as active cycle of breathing techniques, autogenic drainage and forced expiration, can be effective in the treatment of COPD. The evidence for passive techniques such as postural drainage and percussion is low. There is little evidence for other supporting techniques such as intrapulmonary percussive ventilation, positive expiratory pressure and non-invasive ventilation because of the small number of studies. Functional imaging (17) was used to determine whether chest physiotherapy enhances sputum evacuation in COPD patients in combination with intrapulmonary percussive ventilation (IPV). During an acute exacerbation, five moderate to severe COPD patients (three females and two males; mean forced expiratory volume in 1 second of 39.49% predicted) who were admitted to the hospital were included in this study. One hour before IPV, lung function measurements, arterial blood gas sampling and a 3D low-dose CT scan were performed; all were repeated after treatment. No significant changes were noted in the lung function parameters or arterial blood gases. With computational fluid dynamics, specific airway resistance was calculated for different branches in the airways; none of the changes were statistically significant. There were local changes in airway resistance. Functional imaging allows the calculation of the changes in
local airway resistance and the local changes in airway volume in COPD patients to evaluate the effect of IPV.
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Studies predicting postoperative lung function Before performing a surgical resection of non-small cell lung cancer, it is important to obtain an accurate estimation of post-operative (po) forced expiratory volume in 1 s (FEV1). When the pre-operative FEV1 or diffusing capacity for carbon monoxide is 9%.
Acute effects of intrapulmonary percussive ventilation in COPD patients assessed by using conventional outcome parameters and a novel computational fluid dynamics technique. Int J Chron Obstruct Pulmon Dis 2012; 7: 667-671
Five moderate to severe COPD patients
To visualize the shortterm effects of a single IPV treatment in COPD patients.
No significant changes were noted in the lung function parameters or arterial blood gases measured within 1 hour after the end of the IPV session.
To detect changes in the airway patency after the IPV treatment compared with before treatment.
Estimation of post-operative forced expiratory volume by functional respiratory imaging. Eur Respir J 2015; 45: 544-546.
single-centre, prospective pilot study enrolled consecutive patients with early-stage NSCLC that was considered resectable and scheduled for lobectomy/pneumonecto my. Case report of 2 patients with idiopathic unilateral diaphragmatic paralysis.
To evaluate a precise tool to estimate poFEV1.
PpoFEV1FRI was c comparing with two current standard techniques, gives the same results
Better prediction is due to the fact that patient-specific, regional differences in airway resistance and tissue compliance
To evaluate the clinical value of FRI in patients with idiopathic unilateral diaphragmatic paralysis
With FRI analysis it is possible to revealed that there is regional ventilation, to choose the right treatment plan
Demonstrates the potential of FRI as a new functional imaging technique in respiratory medicine to choose the right treatment plan in patients with idiopathic unilateral diaphragmatic paralysis
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Functional Respirator Imaging as a tool to personalize respiratory treatment in subjects with unilateral diaphragmatic paralysis. Respir Care 2013.
ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20
Functional respiratory imaging (FRI) for optimizing therapy development and patient care Bita Hajian MD, Jan De Backer PhD, Wim Vos PhD, Cedric Van Holsbeke PhD, Johan Clukers MD & Wilfried De Backer MD, PhD To cite this article: Bita Hajian MD, Jan De Backer PhD, Wim Vos PhD, Cedric Van Holsbeke PhD, Johan Clukers MD & Wilfried De Backer MD, PhD (2016): Functional respiratory imaging (FRI) for optimizing therapy development and patient care, Expert Review of Respiratory Medicine, DOI: 10.1586/17476348.2016.1136216 To link to this article: http://dx.doi.org/10.1586/17476348.2016.1136216
Accepted author version posted online: 05 Jan 2016.
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Date: 26 January 2016, At: 02:44
Publisher: Taylor & Francis Journal: Expert Review of Respiratory Medicine DOI: 10.1586/17476348.2016.1136216
Functional respiratory imaging (FRI) for optimizing therapy development and patient care Review
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Bita Hajian, MD1; Jan De Backer, PhD2; Wim Vos, PhD2; Cedric Van Holsbeke, PhD2; Johan Clukers, MD1;Wilfried De Backer, MD, PhD1
1
University Hospital Antwerp, Department of Respiratory Medicine, Belgium
2
FLUIDDA nv, Belgium
Corresponding author: Bita Hajian Wilrijkstraat 10 2650 Edegem Belgium Tel: Email: [email protected] Abstract: 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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KEYWORDS: COPD FRI, phenotype, personalized treatment INTRODUCTION Large-scale clinical studies using a number of inhalation compounds and fixed combination products have been performed with spirometric values as the primary endpoints, primarily including the forced expiratory volume in 1 second (FEV1), as well as the Saint George Respiratory Questionnaire (SGRQ). The FEV1 is still considered the gold standard for the functional assessment of airway diseases both in clinical settings and in pharmacological research. The FEV1 is a dynamic lung volume obtained one second after the start of a forced expiration. The SGRQ questionnaire is a standardized self-completed questionnaire for measuring impaired health and perceived wellbeing ('quality of life') in airway disease. It was been designed to allow comparative measurements of health between patient populations and to quantify changes in health following therapy (1). Many clinical studies (2) indicate changes in respiratory parameters after the administration of the investigated product; however, the clinical significance of these changes is not clear, and the measured parameters are occasionally below the lower limit of reported clinical significance (3). For example, although an overall maximum change in FEV1 of 150 ml was observed, the clinical implication of this value remains uncertain. In addition, regarding the outcome of the SGRQ, the studies often only demonstrate a maximum change of approximately 4, which is recognized as the lower limit for clinical significance; there is typically a weak correlation between SGRQ and FEV1 (4).
In contrast, the prevalence and mortality of respiratory diseases are increasing, with more than 500 million estimated patients. Thus, an unmet need for additional sensitive outcome parameters exists, beginning with outcome parameters that would assist in understanding the mode of action and subsequent pharmacodynamic effect. In this review, we discuss the application of functional respiratory imaging (FRI) to obtain a better understanding of the pathophysiology of respiratory diseases and to optimize therapy development and patient care. FUNCTIONAL RESPIRATORY IMAGING (FRI) AS A BIOMARKER In recent years, imaging of the thorax has evolved substantially from an experimental tool that was used in only a limited number of centers towards becoming a routine test for clinical assessment of the respiratory system. In particular, the development of computed tomography (CT) has greatly increased the understanding of the pathophysiology of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). The imaging method itself has been increasingly used in clinical trials, although the absolute number of studies remains limited. Without additional post processing, a CT scan is limited to static information about the respiratory system. This in itself is already very valuable because, due to the high resolution of CT, certain pathologies (e.g., fibrosis and bronchiectasies) can be distinguished very well.
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Today, CT is the method of choice to determine the extent of emphysema in COPD patients by measuring lung density. Recent developments in the field of flow and structural simulations have made it possible to simulate the behavior of airway flow in a patient in a specific fashion based on the CT images using a method called computational fluid dynamics (CFD). It could therefore be hypothesized that functional parameters derived from patient-specific simulations, such as the modeled airway resistance, can function as a biomarker. Changes in this biomarker could be a reflection of changes that are clinically relevant and are even more sensitive to changes than classical lung function measurements are. FRI also provides regional information and allows for measurable changes at the level of the lobes and airways. In addition, there is the possibility of describing particles in the airflow and airway as well as the lung deposition of the inhaled compounds. Because patients only underwent CT scanning, the procedure is minimally invasive and almost without risk. Radiation exposure nevertheless is a risk, but scan protocols with limited radiation exposure are possible. A typical radiation dose consists of 1-2 mSv per scan (6). This means that the radiation dose is 3 times less than a “classical” CT, which usually has a dose of 10-12 mSv. Because of the low radiation dose, repeated scans in clinical follow-up or in clinical studies can be performed without increasing the radiation dose above the exposure that is currently used for routine examinations. It can be expected that further developments in CT scanners will reduce the radiation even further (7). Using a lower dose can increase the level of noise in the scan. However, this can be mitigated by using appropriate filters and iterative reconstruction algorithms. In addition, the natural contrast between the air and the surrounding tissue allows for a significant reduction in the dose while maintaining the image quality. The radiation dose of CT scans in clinical practice has also been decreased due to these technological innovations. Thus, we believe that the quantification of CT scans through methods such as Functional Respiratory Imaging can become routine for specific applications in a patient population suffering from lung diseases. FRI is essentially a composite biomarker because it includes data concerning lobar volumes, airway volumes, airway resistance and aerosol deposition. With increasing experience with the method, it will become clear what the minimal significant clinical difference for the subsets of parameters will be. For drug development, it can already be used to understand the mode of action, whereas in clinical settings, information about regional airflow distribution and related lung structure and vascularization is obtainable. This is of utmost importance to understand ventilation-perfusion ratios and the effect of interventions or spontaneous fluctuations in this parameter over time.
MEASUREMENT METHODOLOGY OF FRI Functional Respiratory Imaging is a proprietary workflow that was developed and validated by FLUIDDA. The FRI workflow is a combination of several software components and is provided by the company as a service.
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CT scans are taken as mentioned before using a dose reduction protocol (120 kV, 10–100 mAs; noise factor 28; collimation 0.625 mm; rotation time 0.6 sec and pitch factor 1.375) resulting in an effective dose of 1-2 mSv per CT scan. The scan resolution is 0.5 mm3, and the slice increment is 0.6 mm. Scans are taken at two different levels: functional residual capacity (FRC) and total lung capacity (TLC) (Fig 1.). To ensure the correct lung volume, CT scans are respiratory volume gated during the moment of scanning using a pneumotach flow signal.
Figure 1. Signal from respiratory gating to ensure adequate total lung capacity (TLC) and functional residual capacity (FRC) levels to reduce clinical variability.
Subsequently, CT images are segmented using a segmentation program that has been cleared by the FDA’s Center for Devices and Radiological Health (CDRH) under the 510(k) process (Food and Drug Administration, K073468) and has been CE marked in Europe (Conformité Européenne certificate, BE 05/1191.CE.01). This program converts CT images into patient-specific reconstructions of the lung lobes and the airway tree. By segmenting lung lobes at the FRC and TLC, the internal airflow distribution can be derived from the relative volume change. The airway tree is normally evaluated at the TLC level because doing so eliminates the effects of breathing level. At the TLC, the airway structure can be segmented down to the bronchi, with a diameter of approximately 1-2 mm. Beyond this point, the CT resolution is insufficient to distinguish alveolar and intraluminal air. A typical airway model includes 5-10 generations that depend primarily on the disease state of the individual patient. Distal airway volumes (iVaw) can be assessed at individual airways or in different regions.
The smoothed airway reconstructions are subsequently trimmed at the trachea and the terminal bronchi to obtain a model that is suitable for flow simulation. Next, these segmentations are exported to a meshing software package, where they are divided into discrete tetrahedral elements. Flow properties are obtained throughout the flow domain by means of computational fluid dynamics (CFD). The outflow to each lobe is adjusted iteratively for each patient to match the internal flow rate distribution obtained from the CT scans (6,7,8). Measures of resistance (iRaw) in individual airways or different regions corresponding to the volume measurements are obtained from CFD calculations. Resistance is defined as the total pressure drop over an airway divided by the flow rate through that airway. In a typical clinical trial, the imaging procedure will be performed at baseline and after the intervention. Subsequently, the resulting models are overlaid and compared to one another to establish the changes induced by the therapy. APPLICATION OF FRI IN CLINICAL TRIALS
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Virtually all therapies for lung diseases are aimed at changing lung geometry. Bronchodilators and anti-inflammatory compounds are developed to increase the airway lumen. The former does this through smooth muscle relaxation, and the latter does so through inhibition of inflammation. The resulting improvement in lung geometry is a consequence of ameliorated lung function. Patients should breathe better if the therapy is successful. Eventually, breathing better should result in an improved quality of life (QOL). Today, quality of life is assessed using questionnaires or patient-reported outcome parameters (PRO); lung function is usually analyzed via spirometry and body plethysmography. The geometry can be evaluated using imaging modalities such as computed tomography (CT) and functional respiratory imaging (FRI). When considering the three categories (geometry, lung function and QOL), the inherent number of confounding factors increases from geometry over lung function to QOL (Figure 2). For instance, the conventional pulmonary function tests, such as spirometry, measure not only the characteristics of the tracheobronchial tree (lower airways, where the intervention is designed to act) but also the extrathoracic airway (upper airway) characteristics, the muscle force and the patient’s effort. The questionnaires inherently include the effects of comorbidities and depend on the patient’s concentration and willingness to cooperate. With an increased level of confounding factors, the variability of the measured outcome parameter increases, leading to a larger required sample size of the clinical trials. The correlations between the different categories, although significant (p < 0.05), are often weak (low R) due to the large variability in the outcome measure, as described in the next section. By providing information closer to the site of action, imaging and FRI should be able to provide higher signal-to-noise outcome parameters. FRI focuses on the region of interest and the site of action (usually the tracheobronchial region) and thereby eliminates the noise and variability induced by upper airway resistance and compliance, muscle force and patient effort. Thus, by using FRI outcome parameters, the same statistical significance can be achieved with fewer patients. This in turn makes it possible to use clinical trials as a design tool and not as a mere assessment tool. This offers a rationale for using FRI in clinical studies but also in daily praxis, especially in difficult cases where regional information might be helpful in choosing the most adequate treatment approach. In our clinic, we use FRI routinely in patients with COPD gold C and gold D, in patients with diaphragm paralysis and before lung transplantation. We now overview a number of clinical trials in which FRI has been used successfully to elucidate the mode of action or the intervention effect with a higher sensitivity. FRI involves the visualization of anatomical structures, such as airways, lobe volumes and blood vessels, in 3D and adds functionality to these images by means of computer-based flow simulations. Its advantage over the conventional imaging approach, where a radiologist describes the findings, is that FRI quantifies the anatomical structures. In other words, the 3D visualization is expressed in numbers (e.g., airway volume, blood vessel volume) that allow for a highly detailed follow up in terms of disease progression or assessing the effects of interventions. The flow simulations use so much patient-specific information (e.g., airway geometry, internal airflow distribution, inhalation profile) that they provide an accurate idea of the regional resistance and deposition patterns. These parameters cannot be obtained using conventional imaging approaches. The additional benefit of FRI compared to conventional pulmonary functional testing is described in Table 1. Both asthma and COPD patients were studied. Both bronchodilators and antiinflammatory compounds were studied and in both conditions. The rationale for each study is explained, and the main results are summarized.
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Figure 2. Cascading effect of lung interventions (from changes in geometry to better lung function and quality of life) and the associated confounding factors and required sample size.
Studies in asthma using bronchodilators The first study looked at the acute effect of a LABA in asthmatic patients (8). In that study, 14 mild to moderate asthmatic patients were studied. Ten patients in the active group underwent HRCT before and 4 h after the inhalation of a novel long-acting beta (2) agonist (LABA) that acts shortly after inhalation. Four patients in the placebo group were studied for chronic effects and underwent CT scans twice after adequate washout of bronchodilators. In the active group, a significantly increased bronchodilator response was seen with a forced expiratory volume in 1 s (FEV1) of 8.78 +/- 6.27% predicted vs. -3.38 +/- 6.87% predicted in the control group. The changes in FEV1 correlated significantly with the changes in the distal airway volume (r = 0.69, p = 0.007), total airway resistance (r = -0.73, p = 0.003) and distal airway resistance (r = -0.76, p = 0.002), as calculated using the CFD method. The changes in distal R (aw) were not fully homogeneous. In some patients with normal FEV1 at baseline, CFD-based changes in R (aw) were still detectable. Interestingly, although FEV1 correlated well with the changes in geometry, the latter were far more pronounced than the changes in FEV1. This provided an initial confirmation that FEV1 can underestimate the real geometrical changes. In Figure 3, the color code indicates the changes in airway caliber after LABA as well as the changes in airway resistance. It can be seen that the changes do not occur homogeneously. There is both central and peripheral bronchodilation. The differences in sensitivity can also be seen in Figure 4, where the changes in FEV1/FVC are much smaller than those in the imaged airway volumes and resistances.
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Figure 3. Illustration of the changes in volume (%) and resistance (%) post bronchodilation for a chronically treated patient. (Ref 8: Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation, J Biomech 2008)
Figure 4. Significant correlation between the tiffeneau ratio (%) and change in distal volume (%) post bronchodilation (Ref 8: Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation, J Biomech 2008)
Studies in asthma using fixed combinations of ICS-LABA To gain insight into the mode of action of extrafine beclomethasone/formoterol (BDP/F) in small airways of asthmatic patients using functional imaging (9), 24 stable asthmatic patients were subdivided into three groups (steroid naive, n = 7; partially controlled, n = 6; well controlled, n = 11). All patients were switched from their current treatment to a fixed combination of an extrafine HFA solution of BDP/F. Lung function and HRCT of the thorax were performed at inclusion and after 6 months of treatment with the study medication. A steady normal inspiratory flow of 25 l/min was simulated for all patients to mimic the flow properties at tidal breathing. The outflow to each lobe was adjusted iteratively for each patient to match the internal flow rate distribution obtained from the HRCT scans. There was a significant improvement in asthma control with an increase in the ACT score and in the pre-bronchodilation imaging parameters, including small airway volume (p = 0.0007) and
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resistance (p = 0.011). Changes in the asthma control score (ACT) were correlated with changes in small airway volume (p = 0.004). Exhaled nitric oxide (p = 0.040) and forced expiratory volume in 1 s (p = 0.044) also improved. Compared to lung function tests, functional imaging provided more detail and clinical relevance, especially in the wellcontrolled group, where only the functional imaging parameters showed significant improvement; the correlation with the asthma control score remained. BDP/F extrafine formulation can target areas of the lungs that were left untreated by larger-particle fixed combinations, resulting in a significant reduction of small airway obstruction that was detectable by functional imaging (HRCT/CFD). Compared with FEV1, imaging parameters are much more sensitive to detect changes in larger and smaller airways. Functional imaging is a useful tool for the sensitive assessment of changes in the respiratory system after asthma treatment (Figs 5, 6).
Figure 5. Three-dimensional reconstruction of airway structure from HRCT images showing central (gray) and distal (red) airways. (Ref 9: Novel functional imaging of changes in the small airways of patients treated with extrafine beclomethasone/formoterol, Respiration 2013)
Figure 6. Correlation between changes in image-based airway volume (iVaw) and the change in asthma symptom score (ACT) for well-controlled patients. (Ref 9: Novel functional imaging of changes in the small airways of patients treated with extrafine beclomethasone/formoterol, Respiration 2013)
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Studies in COPD using bronchodilators With functional imaging, it is possible to compare the bronchodilating effects of salbutamol and ipratropium bromide in the central and distal airways in patients with chronic obstructive pulmonary disease (COPD). To show this, five patients with Global Initiative for Chronic Obstructive Lung Disease Stage III COPD were randomized to a single dose of salbutamol or ipratropium bromide in a crossover manner, with a 1-week interval between treatments (10). Lung function and a multislice computed tomography scan of the thorax was performed before and two hours after dosing. Central but primarily distal airway dimensions (third to seventh bifurcation) increased significantly after an inhaled beta2agonist (salbutamol) and anticholinergic agent (ipratropium bromide) in patients with severe COPD. The changes observed upon lung function testing were, overall, less pronounced than the changes in airway caliber seen by the imaging method. Salbutamol and ipratropium bromide were equally effective at first glance when looking at lung function tests, but when viewed in more detail with functional imaging, hyporesponsiveness could be shown for salbutamol in one patient. Salbutamol was more effective in the other patients. This pilot study showed that the new techniques of functional imaging and computational fluid dynamics give innovative insight into the modes of action of salbutamol and ipratropium bromide in patients with COPD.
Studies in COPD using fixed combinations of ICS-LABA As with asthmatic patients, functional respiratory imaging was used. This study (11) looked at the effect of ICS in steroid-naïve mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients who had previously used ICS when switching to an extrafine particle beclomethasone/formoterol. Conventional pulmonary function tests, patient-reported outcomes and novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and computational fluid dynamics, were used. The study showed that the administration of extrafine beclomethasone/formoterol after 46 hours 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 at the lobar level in total lung capacity was significantly reduced (-1.19±7.19%p, p=0.009). A significant improvement in the SGRQ symptom score was noted in the entire patient population. A decrease in hyperinflation was compatible with improvement in the MMRC dyspnea score. Comparing FRI before and after treatment, there was a significant difference in regional deposition between extrafine and nonextrafine formulations, with -11% extrathoracic deposition and up to +4% lobe deposition for the extrafine formulation. FRI is a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry (11,12, Table 1). Airway and lobe volumes are direct measurements from the CT data that are obtained through segmentation, whereas the CFD method is used to
determine airway resistance and aerosol deposition characteristics. Having the opportunity to assess parameters on a lobar scale is a significant improvement over the existing techniques, such as spirometry and body plethysmography, which typically use a black box approach.
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Studies on COPD using N-Acetyl Cysteine There is also increasing evidence that oxidative stress in COPD patients will lead to the production of proinflammatory cytokines and growth factors. The transmigration of neutrophils into the lung tissues and abnormal activation are responsible for the overproduction of reactive oxygen species and the release of proteolytic enzymes in the lungs. It is interesting to understand the role of inflammatory compounds and which patients respond to them. A total of 12 COPD GOLD II patients were included (13). Patients were randomized to receive a daily dose of 1800 mg of NAC (N-acetyl cysteine) or placebo for three months, after which they were crossed over to the other arm for another 3-month treatment period. Significant correlations were found between the image-based resistance values and glutathione (GSH) (p=0.011) and glutathione peroxidase (GPx) (p=0.017). Imagebased resistance values appeared to be a good predictor for GSH levels after NAC treatment (p=0.02), changes in the GPx level (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 on the same order as the changes induced by budesonide/formoterol. A combination of GSH, GPx and imaging parameters could potentially be used to phenotype patients who would benefit from the addition of NAC to their current therapy. It appears that patients with low GPx levels at baseline have room for improvement when using anti-oxidant therapy, and these patients appear to be the responders when N-acetyl cysteine is administered. Again, it is important to identify the responder phenotype. The findings of this small pilot study need to be confirmed in a larger pivotal trial.
Studies in COPD using Roflumilast Roflumilast has been added as a therapeutic option for severe COPD patients. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor. The current study aims to assess the mode of action of Roflumilast as an add-on to LABA/LAMA/ICS therapy in severe COPD patients. Forty-one patients were randomized to receive Roflumilast or placebo (14). At baseline and after 6 months of treatment, pulmonary function tests, exercise tolerance tests and functional respiratory imaging (FRI) were performed, and patient-reported outcomes (PRO) were measured. A significant improvement in FEV1 of 66±120 ml (p=0.01) was observed in the Roflumilast group compared to baseline. In the placebo group, the FEV1 declined by -59±71 ml. The response was driven by a subset (n=8) of responders with a change in FEV1 that exceeded its measurement error of 120 ml. The responders experienced worse dynamic hyperinflation during exercise at baseline than did the non-responders. FRI parameters indicated regional changes in hyperinflation after treatment with Roflumilast that led to an improvement in PFT, PRO and exercise tolerance. The anti-inflammatory characteristics of Roflumilast seem to reduce inflammation in the smaller airways, which leads to a reduction in hyperinflation and a change in internal airflow distribution (IAD). The change in IAD enhances the deposition of the LABA/LAMA/ICS therapy and leads to clinical improvements. Patients who suffer from dynamic hyperinflation tend to benefit from Roflumilast. These findings need to be confirmed in larger clinical trials.
The study suggests that patients who are prone to dynamic hyperinflation are the responder phenotype, suggesting that Roflumilast reduces inflammation and, hence, hyperinflation in smaller airways.
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Studies in COPD using NIV Less is known about the noninvasive ventilation (NIV) effects of a long-term treatment in hypercapnic COPD and how these factors may predict a response in terms of improved oxygenation and lowered CO2 retention. Patients actively treated with NIV developed a more inhomogeneous redistribution of mass flow than did control patients. Subsequent analysis indicated that in NIV-treated patients who improved their blood gases, mass flow was also redistributed towards areas with higher vessel density and less emphysema, indicating that flow was redistributed towards areas with better perfusion. A significant correlation has been found between the percentage increase in mass flow towards lobes with a blood vessel density of >9% and the increase in PaO2. The improved ventilation–perfusion match and recruitment of previously occluded small airways can explain the improvement in blood gases. In hypercapnic COPD patients treated with long-term NIV over 6 months, a mass flow redistribution occurs (Fig 7), providing a better ventilation–perfusion match. Control patients improved homogeneously in airway volumes and local airway resistance, without improvement in gas exchange, because there was no improved ventilation/perfusion ratio or increased alveolar ventilation. These differences in response can be detected through functional imaging, which gives a more detailed report on regional lung volumes and resistances than classical lung function tests do. It is possible that only patients with localized small airway disease are good candidates for long-term NIV treatment. To confirm this and determine whether better arterial blood gases also lead to better health related quality of life and longer survival, a larger population must be studied. This study (15) generated the hypothesis that COPD patients benefit from NIV treatment (i.e., are responders) if the treatment redirects incoming air to better-perfused areas. If the NIV treatment does not change the internal airflow distribution or more air is going to areas with less perfusion, then the patient tends to be a non-responder. Internal airflow distribution is based on lobe expansion from expiration to inspiration and can be expressed on a lobar or segmental level
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Figure 7. Mass flow (re)distribution in a patient treated with noninvasive ventilation for 6 months. (Ref 15. The effects of longterm noninvasive ventilation in hypercapnic COPD patients: a randomized controlled pilot study. Int J Chron Obstruct Pulmon Dis 2011)
Studies in COPD using airway clearance techniques A review (16) of the use of different airway clearance techniques (ACT) and their effects in patients with COPD showed that studies that provide solid evidence of the effectiveness of different airway clearance techniques in patients with COPD are rather scarce. A total of 26 articles were included. There is evidence that active breathing techniques, such as active cycle of breathing techniques, autogenic drainage and forced expiration, can be effective in the treatment of COPD. The evidence for passive techniques such as postural drainage and percussion is low. There is little evidence for other supporting techniques such as intrapulmonary percussive ventilation, positive expiratory pressure and non-invasive ventilation because of the small number of studies. Functional imaging (17) was used to determine whether chest physiotherapy enhances sputum evacuation in COPD patients in combination with intrapulmonary percussive ventilation (IPV). During an acute exacerbation, five moderate to severe COPD patients (three females and two males; mean forced expiratory volume in 1 second of 39.49% predicted) who were admitted to the hospital were included in this study. One hour before IPV, lung function measurements, arterial blood gas sampling and a 3D low-dose CT scan were performed; all were repeated after treatment. No significant changes were noted in the lung function parameters or arterial blood gases. With computational fluid dynamics, specific airway resistance was calculated for different branches in the airways; none of the changes were statistically significant. There were local changes in airway resistance. Functional imaging allows the calculation of the changes in
local airway resistance and the local changes in airway volume in COPD patients to evaluate the effect of IPV.
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Studies predicting postoperative lung function Before performing a surgical resection of non-small cell lung cancer, it is important to obtain an accurate estimation of post-operative (po) forced expiratory volume in 1 s (FEV1). When the pre-operative FEV1 or diffusing capacity for carbon monoxide is 9%.
Acute effects of intrapulmonary percussive ventilation in COPD patients assessed by using conventional outcome parameters and a novel computational fluid dynamics technique. Int J Chron Obstruct Pulmon Dis 2012; 7: 667-671
Five moderate to severe COPD patients
To visualize the shortterm effects of a single IPV treatment in COPD patients.
No significant changes were noted in the lung function parameters or arterial blood gases measured within 1 hour after the end of the IPV session.
To detect changes in the airway patency after the IPV treatment compared with before treatment.
Estimation of post-operative forced expiratory volume by functional respiratory imaging. Eur Respir J 2015; 45: 544-546.
single-centre, prospective pilot study enrolled consecutive patients with early-stage NSCLC that was considered resectable and scheduled for lobectomy/pneumonecto my. Case report of 2 patients with idiopathic unilateral diaphragmatic paralysis.
To evaluate a precise tool to estimate poFEV1.
PpoFEV1FRI was c comparing with two current standard techniques, gives the same results
Better prediction is due to the fact that patient-specific, regional differences in airway resistance and tissue compliance
To evaluate the clinical value of FRI in patients with idiopathic unilateral diaphragmatic paralysis
With FRI analysis it is possible to revealed that there is regional ventilation, to choose the right treatment plan
Demonstrates the potential of FRI as a new functional imaging technique in respiratory medicine to choose the right treatment plan in patients with idiopathic unilateral diaphragmatic paralysis
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Functional Respirator Imaging as a tool to personalize respiratory treatment in subjects with unilateral diaphragmatic paralysis. Respir Care 2013.
