Quantification of the local distribution of gas trapping is achievable by the determination of the percentage of lung voxels <−856 HU (Exp−856) on expiratory CT scans. If paired inspiratory and expiratory scans are acquired, the ratio of expiratory to inspiratory mean lung attenuation (E/I MLA) can be used as a further gas-trapping measure. These 2 approaches are markers of small airway disease in smokers with and without COPD but are not able to separate gas trapping due to emphysema from gas trapping due to small airway disease.11,18 Another technique tries to exclude emphysematous areas and determines the difference between the relative lung volume change in the attenuation range of −950 to −856 HU on expiratory and inspiratory scans (RVC856-950); the lower threshold was adopted to eliminate the influence of emphysema; it has been shown that this index correlated closely with airway dysfunction in COPD regardless of the degree of emphysema.11,18
A computationally more complex approach is the parametric response map (PRM) method developed by Galbán and colleagues, a voxel-wise image analysis technique that does not only require segmentation but also registration for assessing the COPD phenotypes.19 The PRM method spatially aligns the expiratory to the inspiratory scan by a deformable volumetric registration process. Thereafter, the classification of lung voxels can be carried out by using the expiratory and inspiratory attenuation value for every voxel. This allows classifying lung voxels as normal parenchyma (PRMNormal), functional small-airway disease (PRMfSAD), and emphysema (PRMEmph) (Fig. 4). Galbán’s PRM method has been integrated with advanced registration techniques in commercial software systems like the Lung Density Analysis (LDA) software (Imbio, LLC, Minneapolis, MN), the Pulmonary Workstation 2.0 (VIDA Diagnostics, Coralville, IA), the LungQ software (Thirona, Nijmegen, Netherlands), or the research software system YACTA (University of Heidelberg, Heidelberg, Germany). It has been shown in multiple studies that PRM serves as a valuable measure of disease. The COPDGene and SPIROMICS studies have both integrated PRM as part of their trials.20,21 Further processing is available for quantification of air trapping from paired inspiratory and expiratory scans with adjustment of CT image quality problems.22
Another way to quantify the contribution of airway disease in COPD is the direct analysis of the airway tree on inspiratory CT scans. For this, the lumen of the tracheobronchial tree will be segmented, the skeleton of the segmentation determined, and a graph representation of the airway tree generated. Thereafter, the airways can be labeled according to the lobes they belong to. The direction vector of an airway is calculable by the underlying graph representation and the skeleton. Thus, it is possible to calculate orthogonal planes for every airway, more precisely for every skeleton point.5,23–25 Lumen, wall thickness, and wall percentage values can be determined for the whole tree at every skeleton position, that is, generation specific. An elegant way to condense the amount of the generated data into an aggregated metric is to calculate the wall area for a theoretical airway with an internal perimeter of 10 mm (AWT-Pi10) by regression analysis.26 Average values for the whole tree and for the individual lobes can be determined for AWT-Pi10 and wall percentage values. Taper index calculation allows the quantification of bronchiectasis25 (Fig. 5). All presented imaging biomarkers are potentially useful for therapy monitoring, and there is yet no consensus on which are most useful. Importantly, both low-attenuation areas and airway wall remodeling on QCT contribute additively to clinical disease severity measured by the BODE index in COPD,27 and both also independently increase the risk for COPD exacerbation.28 The PRM approach further revealed that toward higher GOLD stages, the relative contribution of air trapping decreases, whereas the emphysema percentage rises.19 These key studies emphasize the importance of quantitative postprocessing for imaging-driven research on COPD pathophysiology, not accessible by other noninvasive techniques.
QCT has several limitations that affect quantification of emphysema and also airway geometry. As a limitation related to the imaging technique as such, CT cannot distinguish between mucus and inflammatory airway wall thickening.23 QCT of the airways is relatively robust against variations in radiation exposure and use of iterative reconstruction, for example, in low-dose CT,29 whereas emphysema values are influenced by radiation exposure.30 Quantitative postprocessing of both the parenchyma and the airways is significantly affected by reconstruction kernels (soft vs. sharp),31 reconstructed slice thickness,32 presence of contrast material,33–35 and also the type and manufacturer of the CT scanner,32 as well as the actual software algorithm being used.12,36 Further, the results depend on the inspiration level.32,37 This effect can be reduced by using spirometrically monitored CT acquisition38 and normalizing the results to the individual lung volume.39 Subsequently, efforts are ongoing to broadly standardize QCT by specific acquisition protocols and reference phantoms, for example, by the SPIROMICS and QIBA initiatives.40 In this context, the utility of QCT for COPD phenotyping was demonstrated in the multicenter project EvA (Emphysema vs. Airway disease).39 It was shown that standardization of QCT, achieved by adjusting lung density measurements for lung volume followed by a phantom-based approach, is of critical importance when imaging is acquired from different scanners. The standardization procedure improved the separation of emphysema-dominant from airway-dominant COPD in automated imaging-based phenotyping. However, standardization at present is mainly focused on CT acquisition, and yet does not comprise the software used. Airway walls are small structures compared with the resolution of clinical CT scanners, and, with regard to the different computational algorithms used to segment the airways, simple techniques such as the full width at half maximum method consistently underestimate luminal dimensions and overestimate wall dimensions, and more sophisticated methods provide more accurate measurements but cannot solve this problem completely.24,41
A relatively new—and even less standardized—approach toward quantifying lung destruction in COPD aims at detecting changes in large and small lung vasculature. For example, investigators of the MESA study with 2303 participants unselectively quantified the total pulmonary vascular volume and found that a lower vascular volume was associated with a lower cardiac output and dyspnea.42 Although the peripheral pulmonary vasculature, determined by the cross-sectional area of vessels <5 mm2, may hypothetically decrease in parallel to increasing emphysematous destruction in COPD, the interaction may be more complex and may also depend on hypoxic pulmonary vasoconstriction.43,44 As main pulmonary arterial enlargement, in contrast, is associated with COPD exacerbation and mortality,45 it will be critical to study the changes on the different levels of vasculature just as it is required in airway quantification.
In the last 15 years, various endoscopic techniques were developed, extending the therapeutic spectrum for patients with advanced COPD and emphysema. The physiological effect of the various ELVR techniques is comparable to that of LVRS but with a potentially better risk profile. The success of the different endoscopic treatment modalities depends on precise patient selection. Moreover, an estimated half of the emphysema patients will not benefit from any interventional techniques and should be excluded from these therapeutic modalities. The decision for an invasive treatment approach and the type of intervention (endobronchial therapy, LVRS) should be discussed for each individual emphysema patient within the context of a multidisciplinary team including pneumologists, radiologists, and thoracic surgeons.
The severity of airflow limitation, hyperinflation, emphysema distribution, and interlobar fissure integrity present the key factors that contribute to the decision for an invasive treatment approach. The most important examinations to identify candidates for endobronchial emphysema therapies or LVRS include body plethysmography and high-resolution CT.47 Symptomatic emphysema patients despite maximal pharmacological therapy with a FEV1 between 20% and 45% predicted and a residual volume >175% predicted may be considered as candidates for any interventional therapy. Moreover, noncontrast volumetric CT scan with a slice thickness of 0.5 to 1.25 mm and overlapping reconstructions is required to characterize the emphysema severity, emphysema distribution, and interlobar fissure integrity that is a surrogate for interlobar collateral ventilation (CV), as described below (Table 1).
In general, the endoscopic interventions that aim at hyperinflation reduction are divided into blocking and nonblocking ELVR techniques that aim at hyperinflation reduction. The blocking technique is represented by the reversible valve therapy, whereas the nonblocking technique includes the coil therapy, the polymeric lung volume reduction (PLVR), and bronchoscopic thermal vapor ablation (BTVA). One of the most important differences between the blocking and the nonblocking devices is their dependence on interlobar CV. Although only patients with a complete fissure and thus absent CV will benefit from valve therapy, patients with an incomplete fissure and thus significant CV do not benefit from valve treatment, as the occluded lobe can be backfilled through the collateral channels. In this context, incomplete interlobar fissures are frequently observed on CT scans among the general population with 17% to 85% for the right major fissure, 19% to 74% for the left major fissure, and 20% to 90% for the minor fissure and allow for substantial air flow to a neighboring lobe.48 Nowadays, a complete fissure that indicates no or negligible interlobar CV is defined as >95% completeness of the fissure between the target and adjacent lobes on at least one axis of the CT scan.48 Besides CT fissure analysis, CV can be quantified endoscopically by using the Chartis Pulmonary Assessment system. Thereby, a catheter with an inflatable balloon at the distal tip is inserted into the targeted lobe. After isolating the most diseased lung lobe by inflating the balloon, the airflow can be measured, and thus CV can be quantified. Besides their distinction in CV dependence, the valve therapy differs from the nonblocking ELVR methods by its reversibility.
By complete occlusion of the most emphysematous lung lobe by 1-way valves, a lobar atelectasis occurs, and it results in the desired partial lung volume reduction in selected emphysema patients with absent interlobar CV (Fig. 6). Two different types of valves in different sizes are available that are distinguished by shape, but both act as 1-way valves. The type of valve and the size of the valve are selected depending on the anatomy and diameter of the bronchi of the target lobe. So far, the efficacy of valve therapy was evaluated in several published randomized controlled trials (RCT).49–57 In the first RCTs, statistically significant improvement of lung function parameters, exercise capacity, and health-related quality of life was observed but was of uncertain clinical importance. In these trials, however, patients were enrolled irrespective of the interlobar CV and/or treated by incomplete occlusion of the lung lobe.49–52 Post hoc analysis, however, identified a complete occlusion of the target lobe and an absent CV as important prerequisites for a clinically relevant benefit following valve placement. Therefore, only patients with absent CV that was confirmed by CT fissure analysis or invasive CV measurement by the Chartis System were enrolled in the recent RCTs that showed the valve therapy to result in clinically relevant benefit.53–57 Moreover, retrospective trials showed that valve therapy is associated with a survival benefit in patients who experienced a lobar atelectasis following valve implantation.58,59 Although valve therapy is a minimally invasive treatment, it can be accompanied by adverse events. The most common complication with a rate of 18% to 29% is a pneumothorax due to lobar volume shift after valve placement that requires a chest tube insertion in the majority of the patients with pneumothorax (Table 1). Valve removal or, in rare cases, surgical intervention may also be necessary for pneumothorax management. Nevertheless, pneumothorax does not seem to impact the clinical status in the majority of patients and is even associated with superior outcome in patients in whom complete lobar atelectasis can be observed after their recovery from pneumothorax.60
Besides the blocking valve therapy, the nonblocking techniques consisting of coil therapy, BTVA, and PLVR aim at hyperinflation reduction in patients with advanced emphysema. The most significant difference to the valve therapy is their independence of CV, but also their irreversibility. The major concern with the nonblocking techniques is the insufficient knowledge about predictors of a successful outcome. The coil therapy consists of implantation of a number of lung volume reduction coils in the target lobe, leading to parenchymal compression, and thus to lobe volume reduction and improvement of lung elastic recoil (Fig. 7). So far, 3 RCTs confirmed the efficacy of coil therapy in improving lung function parameters, exercise capacity, and quality of life.61–63 Although achieving statistical significance, the clinical benefit was nevertheless only modest and of uncertain clinical importance. Therefore, coil therapy should preferably be performed within clinical trials. The BTVA and PLVR are similar endobronchial approaches, as both induce an inflammatory reaction that leads to fibrosis and shrinkage and thus to lung volume reduction. BTVA is a segmental treatment approach in patients with upper lobe predominant emphysema, whereby heated water vapor is installed in the most emphysematous segments. The PLVR uses a synthetic polymer in the emphysematous lung areas to promote inflammation and lung volume reduction. The efficacy of both methods is confirmed in one RCT that indicates encouraging improvements in major COPD outcome parameters.64,65 The most common adverse events following BTVA and PLVR are COPD exacerbations, pneumonitis, and pneumonia. Particularly, PLVR is associated with a high-risk profile that limits its current utility. As the data for BTVA and PLVR are still very limited, these methods should be used within clinical trials.
Besides ELVR, the TLD presents an endoscopic treatment approach that aims at sustainable bronchodilation by ablation of parasympathetic pulmonary nerves. As TLD does not aim at hyperinflation reduction, it may present a treatment modality in patients with airway and emphysema-dominant phenotypes. During an endoscopic procedure, a dedicated catheter is advanced into the main bronchi. Afterward, radiofrequency energy is delivered to ablate the pulmonary nerves. Thereby, TLD is performed bilaterally in both main bronchi in a single procedure. The first trial related to TLD confirmed the safety and feasibility of this technique and demonstrated encouraging efficacy results.66 So far, TLD is still under investigation, and the results of an RCT are still pending.
Novel therapies increase the spectrum of therapeutic options in COPD, but they also require sophisticated diagnostics in terms of preprocedural phenotyping and postprocedural monitoring. In addition to clinical tests providing global information on airflow limitation, CT-based information on the extent of regional hyperinflation, emphysema, airway geometry/stability, and fissure integrity becomes increasingly important for the selection of appropriate treatment for individuals, thus increasing treatment success and avoiding unnecessary therapies.
With regard to implantation of endobronchial 1-way valves, regional emphysema severity should be reported for individual lung lobes instead of nonanatomic lung regions, as a unilateral upper or lower lobar target with sufficient severity warranting total atelectasis has to be identified, whereas the presence of sufficient emphysema heterogeneity supports the preservation of a less severely affected adjacent ipsilateral lobe (Fig. 6).49 Visual rating scales allow for semistandardized reporting of local emphysema extent in percentage of the lobar and total lung volume.16,67 Quantitative software, however, allows for a more objective assessment, and several software tools have already succeeded in automatic lobar segmentations with subsequent lobar analysis of emphysema and air-trapping extent, even in subjects with incomplete fissures with relatively low bias,12–14 thus improving accuracy in patient selection for clinical studies or selection of treatment (Fig. 7).
A visual assessment of fissure integrity can be easily performed using low-dose noncontrast chest CT scans with thin-section reconstructions. However, due to the disturbance of lung architecture with substantial distortion of fissures, visual assessments solely based on axial images may incorrectly characterize fissural defects. Therefore, additional sagittal and coronal image reconstructions are mandatory. In this context, studies have shown variable (ie, fair to moderate, κ=0.59 to 0.76) interobserver agreement among experienced radiologists concerning the detection of incomplete fissures.16,68 The percentage of incompleteness should be also reported for each fissure. The automatic software was also shown to detect and quantify structural defects of fissures, with similar accuracy as expert radiologists.69 Although CT analyses of fissure integrity represent indirect measurements (ie, surrogate parameters), the extent of CV can be measured directly with endobronchial balloon catheter systems such as Chartis (PulmonX Inc., Redwood City, CA). However, these systems have certain limitations depending on bronchial anatomy. For example, it is challenging to include the B6 bronchus of the left lower lobe in the measurements.70 On comparing Chartis and CT with surgical inspections serving as the standard of reference, both modalities showed a moderate accuracy (71% vs. 76%) for the detection of incomplete fissures.71 Defining completeness as 90% of the fissure being visible and treatment success as lung volume reduction of at least 350 mL, CT and Chartis showed similar accuracy (77% vs. 74%) in the prediction of response to valve treatment.72 Importantly, the response to valve treatment can be predicted more accurately when combining CT and Chartis.48 Valve therapy monitoring is initially performed using high-quality chest x-ray, which can sufficiently show the localization of the valves and the advent of lobar atelectasis, but also complications such as pneumothorax. If clinical benefit does not occur, further imaging with CT is required in order to quantify target lobe volume reduction and to detect valve migration and malpositioning in more detail at 3 or 6 months following valve placement (Table 1).17,60,73,74 Furthermore, a CT scan with contrast medium is recommended if emphysema patients with a valve-induced lobar atelectasis present clinical signs of infection to confirm/exclude postobstructive pneumonia.
Today, an increasing number of pharmaceutical studies on innovative anti-inflammatory or enzyme-inhibiting agents is being performed using quantitative CT or innovative MRI techniques as part of study protocols. In this context, imaging is used not only for patient selection but also for patient monitoring. For example, airway response to anti-inflammatory therapy with Roflumilast has been investigated in a randomized controlled study (ClinicalTrials.gov identifier: NCT01480661) in patients with severe COPD, with quantitative CT of the airways (including air-flow simulations) serving as the primary outcome measure, providing information on airway geometry and function. In a prospective, randomized, placebo-controlled study (ClinicalTrials.gov identifier NCT02722304), the safety and efficacy of alpha1-proteinase Inhibitor (A1PI) augmentation therapy in subjects with A1PI deficiency and COPD is currently investigated, and the primary outcome measures of the study include longitudinal changes in CT lung density. However, therapy monitoring in COPD based on CT measures of emphysema is challenging, as the measured annual emphysema progression rate is relatively low. For example, in the Multi-Ethnic Study of Atherosclerosis (MESA) lung study including >4000 subjects with a high percentage of smokers, the median percent emphysema (threshold, −950 HU) was 3.0% at baseline, and the rate of progression was 0.64 percentage points over a median of 9.3 years.75 A mean annual increase of emphysema (−950 HU) of 1.07% was found by Mohamed Hoesein et al76 in a cohort of 3670 former and current smokers. Smaller studies among COPD patients reported annual progression rates in percent emphysema of up to 1.03 percentage points depending on the smoking status.77–79 Moreover, the magnitude of the reported long-term changes is within the limits of reported short-term variability.80 Interestingly, the smoking status was shown to significantly influence quantitative CT measures of both lung tissue density and potentially airway geometry.79,81 Therefore, such effects of smoking cessation should be considered when using quantitative CT for therapy monitoring. Longitudinal data on quantitative assessments of airway geometry or air trapping are still lacking. However, preliminary data could show therapy response to bronchodilators, indicating that CT-derived imaging biomarkers of airway remodeling for clinical studies addressing the airway-dominant phenotype of COPD might be more effective as endpoints compared with using low-attenuation areas in emphysema-dominant COPD.82
Tracheal collapse in both patients with stable COPD and patients with disease exacerbation is considerably more prevalent than in healthy individuals.83 In this particular phenotype of COPD, common symptoms include dyspnea, constant coughing, inability to raise secretions, and recurrent respiratory infections.84 Hence, it should be part of comprehensive COPD evaluation and management.83 In addition to dynamic CT, awake functional bronchoscopy and pulmonary function studies are recommended in these patients.84 In this context, it was shown that the magnitude of static end-expiratory tracheal collapse (on expiratory CT) does not predict excessive dynamic expiratory tracheal collapse, as it can occur at variable timepoints during the respiratory cycle.85 This can be addressed with cine CT, which nicely depicts dynamic airway collapse but is limited to predefined anatomical positions.86 Low-dose dynamic respiratory-gated multidetector CT (4D-CT) of the whole chest is now readily available to simultaneously assess the dynamic collapse of any part of the tracheobronchial tree, as well as respiratory dynamics.86 It is acquired during regular tidal breathing and provides thin-section reconstruction, low z-axis increment, and low (5%) respiratory increment at low radiation exposure comparable to paired low-dose CT examinations.86 In patients with significant associated symptoms and severe collapse on CT, temporary Y-shaped airway stent implantation can be considered. However, as airway stents are often associated with complications such as secretion retention, stent implantation does not present a definitive treatment in patients with severe airway instability. In case of symptom relief after stent implantation, the stent should be removed, and patients are considered for surgical reconstruction (membranous wall plication) through a right thoracotomy to improve patient symptoms and quality of life.84 Besides, information from 4D-CT may also be useful for the planning of lung volume reduction therapies.
As a critical note, CT-based biomarkers of lung structure and function enjoy increasing popularity, but substantial intercenter variability can be found due to heterogeneity of imaging protocols or imaging equipment, as discussed above.32 Although reported differences resulting from aforementioned factors along the chain of generating quantitative information from image data are rather subtle, they often are within the same order of magnitude as reported longitudinal changes for emphysema or clinically meaningful variations in airway wall metrics.
The differentiation of emphysema-dominant and airway-dominant COPD phenotypes has immediate practical value in routine patient care with regard to therapy selection. A precise morphologic characterization of emphysema severity, distribution patterns, and fissure completeness supported by software-generated quantitative indices are key to assign patients with advanced emphysema to modern mainly endoscopic techniques for lung volume reduction. With regard to earlier stage COPD, it is less clear to which extent quantitative CT plays a role for therapy selection and as an outcome measure, as natural emphysema progression is slow, which makes it a problematic target for drug trials, and longitudinal data on quantitative airway metrics is currently missing, which requires further research in order to set up new endpoints.
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