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Continuous quantitative measurement of the main bronchial dimensions and lung density in the lateral position by four-dimensional dynamic-ventilation CT in smokers and COPD patients

Purpose The purpose of this study was to measure changes in lung density and airway dimension in smokers in the lateral position using four-dimensional dynamic-ventilation computed tomography (CT) during free breathing and to evaluate their correlations with spirometric values. Materials and methods Preoperative pleural adhesion assessments included dynamic-ventilation CT of 42 smokers (including 22 patients with COPD) in the lateral position, with the unoperated lung beneath (dependent lung). The scanned lungs’ mean lung density (MLD) and the bilateral main bronchi’s luminal areas (Ai) were measured automatically (13–18 continuous image frames, 0.35 seconds/frame). Calculations included cross-correlation coefficients (CCCs) between the MLD and Ai time curves, and correlations between the quantitative measurements and spirometric values were evaluated by using Spearman’s rank coefficient. Results The ΔMLD1.05 (from the peak inspiration frame to the third expiratory frame, 1.05 seconds later) in the nondependent lung negatively correlated with FEV1/FVC (r=−0.417, P<0.01), suggesting that large expiratory movement of the nondependent lung would compensate limited expiratory movement of the dependent lung due to COPD. The ΔAi1.05 negatively correlated with the FEV1/FVC predicted in both the lungs (r=−0.465 and −0.311, P<0.05), suggesting that early expiratory collapses of the main bronchi indicate severe airflow limitation. The CCC correlated with FEV1/FVC in the dependent lung (r=−0.474, P<0.01), suggesting that reduced synchrony between the proximal airway and lung occurs in patients with severe airflow limitation. Conclusion In COPD patients, in the lateral position, the following abnormal dynamic-ventilation CT findings are associated with airflow limitation: enhanced complementary ventilation in the nondependent lung, early expiratory airway collapses, and reduced synchrony between airway and lung movements in the dependent lung.


Introduction
Recently, multiple researchers have focused on lung and thoracic movements visualized by continuous scanning by using a 320-row computed tomography (CT) scanner with 160-mm coverage. [1][2][3][4][5] By applying an iterative reconstruction algorithm, it has been demonstrated that ultra-low-dose (ULD) CT (0.16-0.29 mSv) has similar diagnostic capability to low-dose CT (0.92-1.74 mSv) in the field of lung cancer (nodule) screening. [6][7][8][9][10] These ULD settings have gradually been applied to four-dimensional (4D) dynamic-ventilation CT, which enables the observation of a longer respiratory Dovepress Dovepress 3846 nagatani et al cycle with acceptable radiation exposure (~2.4 mSv) for the evaluation of direct invasion by lung tumors into adjacent structures and localized pleural adhesion. 11,12 It has already been reported that an airway point can be tracked and automatically measured using a commercially available software. 13 Furthermore, mean lung density (MLD) values at each image frame of a dynamic-ventilation CT scan can be measured, although the scanned area does not always include the whole lung. 14 Among variable quantitative CT indices, airway luminal area (Ai) and MLD have been shown to be useful for the prediction of airway flow limitation severity in COPD. [15][16][17][18] In addition, based on a strong positive association between MLD and lung volume (LV), 15,19 changes in MLD values can be a surrogate for changes in LV on the dynamic-ventilation CT. By analyzing dynamic-ventilation CT images using these quantitative parameters, a new perspective for airway and lung movements has been recognized: the synchrony between proximal airway Ai and MLD values, which is limited and correlated with airflow limitation in COPD. 14 This phenomenon may reflect abnormal proximal tracheal/ bronchial collapse in association with rapid tension loss in the surrounding structures during early expiration, which is followed by delayed and restricted ventilation in patients with COPD. However, as these previous studies utilized 4D CT data in the supine position only, the effects of gravity or body position on airway/lung movements remain unclear.
The effect of gravity and body position on ventilation has been investigated using apparent diffusion coefficient (ADC) values measured by hyperpolarized 3 He MRI, which can be a useful indicator of inflation level. 20 Based on the observation, ADC values are similar in nondependent (upside) and dependent (downside) regions at volumes of 100% of vital capacity (VC), whereas the dependent-nondependent vertical gradient in ADC values is observed at VC volumes of both 20% and 60% in nonsmokers, indicating that predominant ventilation occurs in the dorsal regions in the supine position. 20 Based on the observation, a change in body posture from supine to lateral/prone positions must make a great influence on ventilation and perfusion during the whole respiration in the lung field. With patients in the lateral position, ventilation is also regarded as predominant in the dependent lung in a physiological state, compared with the nondependent lung. 21 To the best of our knowledge, no previous information on continuous measurements of MLD or Ai of patients in the lateral position has been reported. Based on our observation of dynamic-ventilation CT image, strange airway/lung movements may appear, and impairment in the synchrony between proximal airway and lung movements may occur in the lateral position.
Thus, the purpose of this study was to measure continuous changes in Ai of the proximal airways and MLD using dynamic-ventilation CT with patients in the lateral position and to assess their correlations with spirometric values.

Materials and methods
The Institutional Review Board of the Shiga University of Medical Science approved this study. Written informed consent was obtained from all the enrolled patients. This retrospective study was planned as a supplementary analysis after our previous research, which aimed at evaluating the potential of dynamic-ventilation CT for the preoperative detection of pleural adhesion. 12 All scan data were anonymized and stored in a research computer. This study was also arranged as part of the Area-Detector Computed Tomography for the Investigation of Thoracic Diseases (ACTIve) study, an ongoing multicenter research project in Japan.

Patient population
Among 85 consecutive patients who underwent dynamicventilation CT within a week prior to lung surgery between November 2015 and November 2016 and had no or slight pleural adhesions confirmed at surgery, 33 patients were excluded as some part of the main bronchi was located outside of the scanning area. Ten nonsmokers were also excluded because the influence of airflow limitation on lung movement for smokers in the lateral position was focused on in this study. Finally, 42 smokers with both main bronchi completely present in the scanning area were included in this study. All the enrolled subjects had resectable lung cancer or benign pulmonary lesions that were proved pathologically afterward. Among them, 22 were diagnosed with COPD. Table 1 summarizes the patient characteristics.

Dynamic-ventilation CT
Dynamic-ventilation CT was implemented after the routine preoperative protocol for CT examination. The scanning field was set in the lateral position with the unilateral affected lung field placed on the upper side (nondependent lung), mainly because of comparison in the detection performance of pleural adhesion around the targeted lung with transthoracic ultrasound at the operation.
Before the dynamic-ventilation CT, all the patients were instructed to inhale and exhale following a spoken command to give a constant respiratory rhythm, and their breathing was monitored by a radiological technologist. After each patient's breathing was confirmed visually to be synchronized with  Image analysis: lung density measurement on dynamic-ventilation CT Using a commercially available software (Lung Volume Measurement; Canon Medical Systems), the MLD was measured automatically in each frame, and the time curve of the MLD on the dynamic-ventilation CT scans was created. On the time curve, the peak inspiratory (minimum) MLD, peak expiratory (maximum) MLD, ΔMLD EI values (defined as the subtracted value of the peak expiratory MLD from the peak inspiratory MLD divided by the peak inspiratory MLD), and the ΔMLD 1.05 values (defined as the subtracted value of the MLD at the third frame [1.05 seconds] after the peak inspiration divided by the peak inspiratory MLD) were obtained ( Figure 1).

Image analysis: quantitative airway measurement on dynamic-ventilation CT
The following procedures were performed using a commercially available research software (4D Airways Analysis; Canon Medical Systems). First, the continuous image data ∆ ∆ Figure 1 example of continuous measurements of MlD and ai in the dependent lung field. Notes: Both MlD and ai values are plotted in each of the 15 frames (0.35 seconds/ frame). In this patient, the peak inspiratory ai is 146.1 mm 2 , and the peak expiratory ai is 94.3 mm 2 . The Δai 1.05 value is 16.5% (24.2 mm 2 /146.1 mm 2 ), which was calculated between the peak inspiratory frame and the third frame after (1.05 seconds later) and adjusted by the peak inspiratory ai as an ai change in the early expiratory phase. The peak inspiratory MlD is -777 hU, and the peak expiratory MlD is -653 hU. The ΔMlD 1.05 value is 10.2% (-79 hU/-777 hU), which was calculated between the peak inspiratory frame and the third frame after (1.05 seconds later) and adjusted by the peak inspiratory MlD as a density change in the early expiratory phase. Abbreviations: ai, luminal area; MlD, mean lung density.
(320 images/frame× total 13-18 frames, every 0.35 seconds) were synthesized for a Cine-CT series. Second, a tree of the centerlines was created automatically from the trachea to all traceable peripheral bronchi throughout the Cine-CT, on which the anatomical information of the measurement point was sustained and reproduced in each frame. Third, once the operator set a measurement point on the airway centerline in a single frame, the corresponding measurement points in other frames were determined simultaneously ( Figure 2).  Airway Ai was measured continuously at a single point of the main bronchi of both the nondependent and dependent lungs. An operator (YN, 17 years' experience in thoracic radiology) selected the middle point of each bronchus in each frame, and the time curve of the Ai on the dynamicventilation CT scans was created. On the time curve, the peak inspiratory (maximum) Ai, peak expiratory (minimum) Ai, ΔAi EI values (defined as the subtracted value of the peak expiratory Ai from the peak inspiratory Ai divided by the peak inspiratory Ai), and the ΔAi 1.05 values (defined as the subtracted value of the Ai at the third frame [1.05 seconds] after the peak inspiration divided by the peak inspiratory Ai) were obtained ( Figure 1).

spirometric evaluation
Within 1 month of the dynamic-ventilation CT date, all the patients underwent spirometry, including FEV 1 and FVC, in accordance with the American Thoracic Society standards. 23

statistical analyses
Cross-correlation coefficients (CCC; -1,R,1) were calculated between the time curves of the MLD and airway Ai of the main bronchus. If the two time curves were completely opposite in direction over time, the coefficient approached -1. Spearman's rank correlation analyses were performed to assess the associations of the CT indices with the FEV 1 /FVC, the FEV 1 predicted, and a cumulative smoking index. Correlations were compared using the Meng-Rosenthal-Rubin method with Fisher's r-to-z transformation. 24 Measured values for the MLD and Ai were compared between the nondependent and dependent lung fields, between peak inspiration and peak expiration, and between the right and left lateral positions at the peak inspiration, in each of the nondependent and dependent lung fields. A P-value of 0.05 was considered significant. All statistical analyses were performed using SPSS software Version 22 (IBM Corporation, Chicago, IL, USA).

Dynamic MlD measurements
MLD at end expiration was higher than that at end inspiration in both the dependent and nondependent lung fields (P,0.001). During a respiratory cycle, the MLD changed by the mean values of 88.5 and 32.4 HU in the dependent and nondependent lungs, respectively. MLD at peak expiration in the nondependent lung field was lower than that in the dependent lung field (P,0.001). Both ΔMLD EI and ΔMLD 1.05 in the dependent lung field were larger than those in the nondependent lung field (P,0.001). At the peak inspiration, MLD in the dependent lung (right: -809.7±32.4 vs left: -812.3±30.8; P=0.646) and that in the nondependent lung (right: -849.8±33.4 vs left: -851.5±19.6; P=0.703) were similar between the right and left lateral position. The ΔMLD 1.05 did not correlate with FEV 1 /FVC in the dependent lung but did negatively correlate with FEV 1 / FVC in the nondependent lung (r=-0.417, P=0.006). The nondependent/dependent ratio of the ΔMLD 1.05 also showed a negative correlation with FEV 1 /FVC (r=-0.476, P=0.001). ΔMLD EI also correlated with FEV 1 /FVC in the nondependent lung (r=-0.344, P=0.026); however, its correlation was weaker compared with that between ΔMLD 1.05 and FEV 1 /FVC. In the dependent lung, peak inspiratory MLD had a mild positive correlation with FEV 1 /FVC (r=0.448, P=0.003), whereas in the nondependent lung neither peak inspiratory nor expiratory MLD correlated with FEV 1 /FVC or FEV 1 predicted (Table 2).

Dynamic bronchial ai measurements
In total, 1,310 middle points of the main bronchi were analyzed for Ai measurements. Among them, 255 points (19.5%) were minimally modified by the operator. Ai at the peak inspiration was smaller than that at the peak expiration in both the dependent and nondependent lungs. Ai at the peak inspiration in the nondependent lung field was larger than that in the dependent lung field (P=0.019). Both ΔAi EI and ΔAi 1.05 in the dependent lung field were larger than those in the nondependent lung field (P,0.001). At the peak inspiration, right Ai (154.  Figures 3 and 4). These data indicate that the early expiratory collapses of the main bronchi are associated with airflow limitation in COPD (Table 3).

relationship between MlD and main bronchial ai
In the nondependent lung, the ΔMLD 1.05 correlated positively with the ΔAi 1.05 (r=0.465, P=0.002), whereas in the dependent lung field the ΔMLD 1.05 did not correlate with the ΔAi 1.05 (r=0.243, P=0.122).
In the dependent lung, the CCC between the main bronchial Ai and MLD correlated with the FEV 1 /FVC (r=-0.474, P=0.002), whereas in the nondependent lung no significant association was found between the CCC and airflow limitation. These findings suggested that the synchrony between the airway and lung movements was attenuated in association with the degree in the airflow limitation in the dependent lung only (Table 4; Table 4). In the right lateral position, the CCC had a negative association with FEV 1 predicted in the dependent lung field (r=-0.545, P=0.036) and a positive association with FEV 1 predicted in the nondependent lung (r=0.559, P=0.030; Table 4).

Discussion
In this study, we quantitatively assessed dynamic-ventilation CT performed in the lateral position and found the following: 1) although the MLD change in the early expiratory phase (within 1.05 seconds) did not correlate with the airflow limitation in the dependent lung, that in the nondependent lung negatively correlated with the airflow limitation, suggesting that larger early expiratory movements in the nondependent lung are found in patients with more severe airflow limitation; 2) early expiratory collapse of the main bronchus was associated with airflow limitation in both the nondependent and dependent lungs, which has been reported by a few previous studies and was first demonstrated as Table 4 CCCs (between main bronchial ai and MlD) and correlations to clinical indices reproducible quantitative data; and 3) reduced synchrony in the dependent lung between the main bronchial and lung movements was associated with the severity of airflow limitation. Based on these observations, we strongly believe that continuous respiratory movements of the lung and central airways depicted by the dynamic-ventilation CT in the lateral position can bring novel insights into the pathophysiology of COPD, particularly regarding the impact of gravity and body position in ventilation. In this study, the MLD change in the early expiratory phase in the dependent lung did not correlate with airflow limitation. This result seems to be discordant with the excellent positive correlation in the supine position. 14 In addition, as MLD is considered to be a good predictor of airflow limitation and air trapping on static CT scans 18,[25][26][27][28] and the changes in MLD in respiratory cycles can be considered as changes in LV, 14,19 the insignificant correlations between the MLD changes in the early expiratory phase and spirometric parameters seem to be strange. This phenomenon may be attributable to  a decrease in VC of the dependent lung in the lateral position, which can be associated with the mediastinum located upward, compared with the supine or prone positions, or to the presumed physiological difference between the unilateral dependent lung in the lateral position and the bilateral lungs in the sitting position for spirometry. Interestingly, in the nondependent lung, the increase in MLD in the early expiratory phase negatively correlated with FEV 1 /FVC, suggesting that the proximal airway closure is delayed in COPD to obtain larger expiratory lung movements. This was also supported by the nondependent/dependent ratio of MLD change in the early-expiratory phase, which was larger in patients with more severe airflow limitation. In addition, the MLD change in the total expiratory phase also correlated negatively with FEV 1 / FVC. These observations suggest the existence of complementary ventilation in the nondependent lung, which would appear to compensate insufficient ventilation in the dependent lung in patients with COPD to some extent. This indicates that the less affected lung may be placed uppermost in COPD patients in the lateral position to improve ventilation in part when the patient has large atelectasis or pneumonia. If this result is validated by other large study populations in the future, this knowledge would also be applicable to pulmonary rehabilitation in the lateral position and important for better understanding of the pathogenesis of COPD.
Another interesting finding of the current study is that the changes in the main bronchial Ai in the early expiratory phase negatively correlated with FEV 1 predicted in the nondependent and dependent lungs. Moreover, these correlations were stronger compared with ΔAi EI from the total expiratory phase. The meaning of highly collapsed proximal airways observed on conventional CT in COPD patients still remains unclear and controversial. [29][30][31][32][33][34][35] For instance, while the collapsed trachea in the well-collapsed lung on (static) expiratory CT often indicates good lung function, 34,35 the expiratory/inspiratory ratio of middle-sized bronchial Ai positively correlates with airflow limitation. 17 These inconsistent results may be due to differences in respiration levels corresponding to the "suspected" end-expiratory phase. In fact, for the assessment of lobar air trapping, MLD changes from end inspiration to end expiration corrected with the LV decrease were reported to be important. 36 Compared with the previous reports using static inspiratory and expiratory CT scans, the abnormal collapse of the proximal airway during early expiration on dynamic-ventilation CT was first correlated with the airflow limitation in this study. The rapid decrease in proximal bronchial Ai during early expiration detected on dynamic-ventilation CT may be a new indicator for COPD severity. This collapse of the proximal bronchi in COPD would cause a delay in expiration in the peripheral bronchi and result in time lags in the movement among different pulmonary regions. Such early expiratory collapse of the proximal bronchi may be a target for future therapeutic strategies for COPD.
In the dependent lung in the lateral position, reduced synchrony between the main bronchial and lung movements was associated with airflow limitation, which was compatible with the results of a previous study analyzing bilateral lung fields using dynamic-ventilation CT in the supine position. 14 In addition, ΔMLD EI in the dependent lung was demonstrated to be larger as compared with the nondependent lung. In the lateral position, it was demonstrated that gravity affects ventilationperfusion matching, which is independent from the hypoxic pulmonary vasoconstrictive response. [37][38][39] In a previous study addressing the role of gravity in the vascular flow redistribution in the lung during one-lung ventilation for COPD patients, the partial pressure of arterial oxygen during one-lung ventilation in the dependent lung in the lateral position decreased by only about 10% compared with bilateral lung ventilation in the supine position. 38 Although the association of the synchrony between the main bronchial and lung movements with ventilation-perfusion relationship has not been evaluated, reduced synchrony in COPD may lead to partial ventilationperfusion imbalance in the dependent lung field and generate complementary lung movement in the nondependent lung. We speculate that a similar phenomenon might be found in the dorsal region in the lower lung field in the supine position, and disconnection between airway and lung movements would prevent effective gas exchange in the lung. At the end inspiration, more Ai reduction in the dependent lung based on the nondependent lung for the left main bronchus (117.1±38.6 in the dependent and 136.8±54.3 in the nondependent lungs) was observed as compared with the right main bronchus (154.0±50.6 in the dependent and 165.6±52.0 in the nondependent lungs).
Considering the positional relationship between the heart and main bronchus, this result may be probably due to more compression and direct pulsation effects of the heart to the main bronchus in the left dependent lung field. Therefore, in the left lateral position, CCC between the main bronchial Ai and MLD at the left lateral position may be attenuated in the dependent lung field, and complimentary ventilation may occur in the nondependent lung field even for some smokers without airflow limitation, resulting in the attenuated correlation between CCC and FEV 1 /FVC or FEV 1 predicted in the nondependent and dependent lung fields. On the other hand, in the right lateral position, main bronchi in the nondependent lung field may not be affected so much by the heart, which is supported by the result that there was a positive correlation of CCC between main bronchial Ai and MLD with FEV 1 predicted. These issues relevant to the influence of the heart on the proximal bronchial and lung mechanics are crucial and should be assessed in detail in our future study.
There were several limitations in this study. First, because this study was performed as a preliminary study to evaluate the association of the synchrony in MLD and Ai with airflow limitation severity on dynamic-ventilation CT, the total number of enrolled patients was small. Thus, the results of this study should be evaluated further in a larger study population without lung tumors. Second, the scanning area could not include the whole thorax. Although we believed that it was best to substitute the MLD measurement as a surrogate for LV measurement, actual respiratory changes in LV could not be measured. Third, we did not measure the trachea and more peripheral bronchi, mainly because we focused on the comparison of the proximal bronchi between the nondependent and dependent lungs. It has been widely accepted that the airway dimensions or wall thickening in the more peripheral airways has been demonstrated to reflect airflow limitation more precisely. Improvement in the software will enable us to measure more peripheral airways on the dynamic-ventilation CT. Fourth, extra radiation exposure for the dynamic-ventilation CT (~2.1 mSv in this study) may lead to concerns about the application of this method in routine clinical examinations. Although the tube current was fixed at 20 mA in this study, a reduced tube current, such as 10 mA, may be feasible in future studies, particularly in combination with more powerful iterative reconstruction techniques. Fifth, the influence of dose reduction on lung densitometry could not be an ignorable issue in this study. However, in a previous study, MLD measured on chest CT image at considerably reduced dose (10 mA) was demonstrated to be almost equivalent to that at standard dose (240 mA) in identical cases. 40 Therefore, considering the tube current adopted in dynamic-ventilation CT was 20 mA, measurement errors in the lung densitometry are thought to be actually too small to bring a crucial problem to our evaluation. Sixth, the severity of airflow limitation in most of the COPD patients was mild (FEV 1 predicted .80%). Whether or not similar results are obtained in patients with severe degree of COPD is unknown and should be examined in a future study for larger study population of patients with more severe airflow limitation.

Conclusion
In conclusion, dynamic-ventilation CT in the lateral position demonstrated that airflow limitation was associated with reduced synchrony between the proximal airway and lung movement in the dependent lung and enhanced complimentary ventilation in the nondependent lung, in addition to early expiratory, pathological, proximal airway collapse in both the lungs.