Quantitative CT-based structural alterations of segmental airways in cement dust-exposed subjects

Dust exposure has been reported as a risk factor for pulmonary disease. For example, occupational dust exposure has been significantly associated with chronic obstructive pulmonary disease (COPD) [1]. Exposure to desert dust has been correlated with an increased risk of hospitalization for asthma [2]. An association between dust exposure and lung function has been reported via cytological and spirometry findings. In dusty areas near cement plants, the serum mercury level of blood samples was correlated with a decrease in the forced expiratory volume in 1 s (FEV₁) and a risk of obstructive lung disease [3]. In addition, workers exposed to dust working in a cement factory were likely to have a decrease in peak expiratory flow [4]. However, the effects of environmental dust exposure on residents near cement plants have not been studied in detail. In this study, we hypothesize that environmental dust exposure by cements is associated with alterations of quantitative computed tomography (QCT)-based airway structural and functional metrics. Thus, QCT imaging-based variables are used to investigate structural and functional alterations due to dust exposure.

With respect to QCT imaging, few studies have investigated the effects of dust exposure on airway structure and lung function. For instance, coal and gold miners have been found to have a higher prevalence of emphysema compared with control groups [5]. The emphysema score measured by QCT has been associated with construction workers who are heavily exposed to asbestos [6] but not quartz and silica [7, 8]. Many previous studies have been limited regarding fully understanding the effects of dust exposure because they employed only one or a few imaging variables for a small number of subjects. More recently, Marchetti et al. [9] demonstrated that occupational dust-exposed subjects had a greater percentage of emphysema, percentage of air trapping, and wall area. The advanced post-processing of QCT imaging can reveal more airway structure features, such as airway luminal hydraulic diameter (D_h), wall thickness (WT), and bifurcation angle (θ) in proximal airways, as well as parenchymal functional features, including air volume, tissue volume, the determinant of Jacobian (Jacobian), percent functional small airway disease (fSAD%), and percent emphysema (Emph%), through the image registration technique [10]. QCT metrics were able to classify clinically meaningful clusters of asthma [11].

With a comprehensive set of QCT imaging-based metrics, we aim to investigate unique features of airway structure and lung parenchymal function between subjects exposed to cement dust (dust-exposed: DE) and subjects with none or little exposure to cement dust (non-dust-exposed: NDE). The DE and NDE subjects were acquired at two different imaging sites, respectively. Both imaging sites collected two CT images for a subject at functional residual capacity (FRC) and total lung capacity (TLC). To minimize the intersite variability, we employed a fraction-threshold method [10, 12], when estimating parametric response map, i.e., fSAD% and Emph%. Next, to control the intersubject variability due to sex, age, height, smoking history, pack-years, and more, we employed a statistical method, i.e., propensity score matching method [13]. This allows for an objective comparison between two groups.

In this study, with the aid of advanced QCT imaging analysis, we have investigated alterations of the airway structure and lung function at multiscale levels in subjects exposed to cement dust. Most similar studies [1‐5, 8, 9] included patients with pulmonary diseases such as COPD and asthma, whereas for an objective comparison, this study excluded patients with pneumonia, asthma, and COPD to minimize confounding effects due to the pulmonary diseases. We also employed a robust statistical method of propensity score matching to control demographic confounders such as age, sex, height, smoking history, and pack-years. It has been known that imaging protocols between different centers are sensitive when estimating density-based imaging metrics such as Emph%, and fSAD% [22], whereas they are less sensitive on airway size parameters [20]. Therefore, we employed a fraction threshold method to compute the Emph% and fSAD%.

With sensitive QCT imaging metrics, we demonstrated that the airway structures of DE subjects had different features from those of NDE subjects. The DE subjects are characterized by phenotypes of airway narrowing (D_h) at lower-lobes, wall thickening (WT) at all segmental airways, and alteration of branching structure (θ) at central airways. These findings were similarly observed in a previous study where individuals with occupational exposure had an increased airway wall thickness [9]. In the meantime, a multicenter study of former and current smokers using the multi-ethnic study of atherosclerosis (MESA) COPD data reveals that COPD subjects caused by mainly smoking have thinner airway walls [23]. The subjects in this study could be also progressed into COPD later, but these subjects exposed by cement dusts have thickened airway walls. A previous study has reported that exposure to cement dust leads to an increase in airway inflammation [24]. Thus, the distinguished phenotypes on airway walls are likely to indicate different airway pathophysiology.

A recent asthma study by Shim et al. [25] using severe asthma research program (SARP) data has demonstrated an association of airway lumen change between TLC and FRC with a corticosteroid treatment, but there were no investigations of wall thickness and branching angle changes between TLC and FRC. In this study, we computed strains for airway hydraulic diameter, wall thickness, and branching angle. To our best knowledge, this is the first effort of estimating strains at bronchial levels between TLC and FRC. As a result, the DE subjects were found to have the increased stiffness of wall thickness (ε^WT) and bifurcation angle (ε^θ) which could be affected by lung fibrosis and atelectasis, possibly due to the airway inflammation. In particular, the stiffened airways were likely to affect the prevention of airway deformation from FRC to TLC, sustaining the airway skeletal structure at FRC.

Regarding parenchymal functional variables (Table 4), lung volume at TLC, lung volume at FRC, IC, and Jacobian in DE subjects were smaller than NDE subjects. The decreased IC and Jacobian in DE subjects also could indicate a reduction of lung deformation. Especially, the reduction of Jacobian was found to be significantly correlated with ε^θ at RMB (Spearman test R = 0.416, P < 0.005). Based upon our analysis, we presume that the significantly reduced lung volume at TLC was caused by a reduced volume change (Jacobian). This is also possibly correlated with an increased stiffness of airways estimated by ε^WT and ε^θ (Table 3 and Fig. 6). In this study, fSAD% of DE subjects was similar with NDE subject, and Emph% of DE subjects was even lower than NDE subjects (Table 4). This is possibly due to the subgrouping by normal lung function, and also indicates that structural alterations of segmental airways begin earlier than parenchymal functional alterations.

Compared with lung functional metrics, airway structural variables provided very clear differences between the DE and NDE subjects. This implies that dust exposure due to cements was significantly associated with bronchial alterations in segmental scales rather than in parenchymal levels. As the size of cement dust ranges from 0.5 to 5 μm [16], cement particles may be deposited in segmental airways [24, 26, 27]. These features are different from the characteristics of cigarette smoke particles. Sahu et al. [28] demonstrated that the deposition rate of cigarette smoke particles was greater in parenchymal regions than in segmental regions due to the small size of the particles (ranging from 0.01 to 1 μm). A previous study found that smokers with normal spirometry were more susceptible to parenchymal alteration associated with the emphysema score [29, 30]. Whether the structural alterations observed here progress to parenchymal levels, leading to severe air-trapping and emphysema, has yet to be confirmed with a longitudinal study.

This study has several limitations. It was retrospectively designed by utilizing CT images collected at two respective sites. Thus, the findings obtained here were possibly influenced by intersite variability, such as scanner difference. However, as shown in Table 1, the two centers used the same scanner make (Siemens), same inspiratory maneuver (TLC), same expiratory maneuver (FRC), and similar reconstruction algorithms (B30f from KNUH and B35f from CNUH), so consistent regional attenuation, airway diameter, and wall thickness between the two groups are expected [31, 32]. In addition, the percent emphysema and percent fSAD were derived from the method using a fraction-threshold [10] that is a density variation-free method. Therefore, these results were not significantly influenced by scanner differences. In the previous study [20, 33], we already confirmed that different scanner had little confounding effect for QCT analysis with data derived from different sites. Furthermore, dust-exposed subjects could suffer from several pulmonary diseases such as interstitial lung disease and fibrosis which were not indicated by FEV₁ and FVC. Therefore, it was better to include DLCO for the criterion when choosing subjects with normal lung function. Unfortunately, DLCO was not collected in this project, but we excluded any noticeable parenchymal diseases such as fibrosis, asthma, and pneumonia, so we believe that the current features in cement dust exposed subjects remained the same.

In conclusion, with QCT imaging metrics, we demonstrated that DE subjects had unique features of airway structure, especially in segmental airways, compared with NDE subjects. In structural variables, DE subjects showed airway narrowing at lower-lobes, wall thickening at all segmental airways, a different bifurcation angle at central airways, and a loss of airway wall elasticity at lower-lobes compared with NDE subjects. Unlike segmental airways, parenchymal changes were relatively marginal at this stage for subjects with normal spirometry, which may be associated with the large size of cement dust. It has yet to be investigated if airway structural changes are associated with flow structure and particle distribution and deposition, so a future study with computational fluid dynamics is needed.