Study of digital lung three-dimensional imaging technology in early COPD

COPD is characterized by progressive development of airow limitation. Small airway functional and structural disease is considered pivotal in the pathology of early COPD. We used pulmonary function (PFT) and digital lung three-dimensional (3D) imaging technology to detect small airway functional and structural disease that applied for screening early COPD. and in We tested the associations between we by comparing

disease status [7]. The small airway is di cult to assess, due to airway diameter and anatomical position in the lung. Therefore, we need more effective tools to diagnose early COPD.
Digital lung three-dimensional (3D) imaging technology has been an emerging technology for COPD pulmonary function assessment in recent years. The technology of semi-automated image assessment can show emphysema distribution and airway structure change clearly by separating the lung parenchyma and airways from the chest wall and surrounding structure. Hisham Taher et al pointed out that lung density, generations 5 to 7 bronchus parameters could effectively evaluate airway disease [8]. Furthermore, Diana E. Litmanovich et al proved that it could perform comprehensive analysis airway disease and lung ventilation function changes in COPD patients, which was a complement of PFT. At the same time, compared with PFT, it is fast, and accurate, which can be repeated secondary measurement [9]. However, digital lung 3D imaging technology had not been fully popularized in the diagnosis of COPD. Whether 3D computed tomography (CT) and PFT can screen early COPD remains unknown.
The aim of this study is to evaluate small airway functional and structural disease in early COPD. Recently, developed digital lung 3D imaging technology has offered the possibility to make these comparisons in detail and in a more sensitive way than using PFT. We used PFT and digital lung 3D imaging technology to detect small airway functional and structural disease that applied for screening early COPD.

Objectives
The objective of review was to screen early COPD and the details were shown as follows; 1. We explore the relationships between digital lung 3D imaging technology parameters and PFT, and, 2. In order to detect small airway functional and structural disease, we compare digital lung 3D imaging technology parameters and PFT between the observation group and control group.

Patients
This was a prospective study of 136 patients at the 903th Hospital of People Liberation Army from January 2018 to January 2019. The patients whose PFT showed that small airway ventilation dysfunction and FEV1/FVC>70% were grouped into the observation group (n=90), while the patients whose PFT showed normal lung function were grouped into the control group (n=46). The exclusion criteria were as follows: 1) <40 and >70 years old; 2) pregnant woman; 3) comorbid lung diseases such as lung cancer, pneumonia, active pulmonary tuberculosis, pulmonary embolism, or interstitilung disease; 4) previous lung surgery; 5) unable to complete PFT; 6) asthma, severe heart, liver, or kidney dysfunction; or 7) CT quality was insu cient for analysis. The study has been approved by the Ethics Committee of the 903th Hospital of People Liberation Army, and all participants gave informed consent.

Data collection
After enrollment, age, sex ratio, smoking composition ratio, body mass index (BMI) and the number of patients were collected.

CT scanning
Respiratory biphasic CT examinations were performed using a 64-detector CT (Somatom De nition AS; Siemens) with subjects holding their breath at full inspiration in the supine position. Tube voltage was 120 kV, and tube current varied by automatic methods based on slice location and participants' body habitus. The exposure time was 0.5 second, and the matrix size was 512×512 pixels. Images were contiguously reconstructed with a 1 mm slice thickness (with 0.625 mm overlapping), using a standard kernel algorithm.

Digital lung 3D imaging technology
The FACT-Digital lung TM software (DeXin, Xi'an, China) was used to perform semi-automated 3D CT quantitative measurements of the bronchial tree ( Figure 1). The following three steps were taken. First, the skeleton extraction algorithm was used to perform a 3D bronchial segmentation. The skeletons of all tested bronchial generations were automatically extracted and exhibited as a bronchial tree (Figure 1 (a-b)). Second, virtual bronchoscopy was used to synchronously display the cursor position on the axial, coronal, and sagittal images and the bronchial straightened image (Figure 1 (c-f)). The enlarged axial view of the bronchus (Figure 1

Statistical analysis
All data were expressed as `x ± SD. Pearson correlation coe cient (r) describes the degree of linear correlation, which is between −1and 1. When r is less than -0.5 or greater than 0.5, it is believable that there is strong negative or positive correlation between two variables. Statistical signi cance between the two groups was evaluated via student¢s t-test. When P < 0.05, the difference was statistically signi cant.

Comparison of respiratory biphasic bronchial tree between the two groups
Compared with the control group, there were small airway structural disease in the respiratory biphasic bronchial tree, especially in the expiratory phase, as shown in Figure 3.

Status of early COPD
COPD is a serious chronic disease, and is associated with increased morbidity and mortality. It is complex, heterogeneous disease characterized by progressive development of air ow limitation, which has become a major public health problem. Rennard SI et al proposed that early COPD was a period before the disease occurs: the disease had not yet produced all the clinical effects. Early COPD mainly had small airway functional and structural disease, which was different from the early stage of COPD [10]. Small airway functional disease is small airway mild air ow obstruction. Structural disease is small airway chronic in ammation, which causes mild small airway wall thickening [11]. Furthermore, lung function damage progress rapidly in early COPD, but it can slow down the disease progression after drug treatment. Therefore, how to improve the diagnosis of early COPD and guide individualized treatment is important.

The diagnosis of early COPD has controversial
In recent years, the diagnosis of early COPD has been controversial at home and abroad. Fernando J et al proposed early COPD should be studied in those younger than 50 years with 10 or more pack-years smoking history and any of these abnormalities: 1) early air ow limitation (post-bronchodilator FEV1/FVC, lower limit of normal), 2) compatible CT abnormalities, 3) rapid decline in FEV1 ( > 60 ml/yr) that is accelerated relative to FVC " to de ne early COPD [12]. However, some people has suggested different views. Alvar Agusti et al found that many patients who no history of smoking and young age also had limited ventilation function, or clinical symptoms [13]. Moreover, there is no clear evidence of a rapid decline in lung function in these patients.

Using digital lung 3D imaging technology to resolve disputes
Now, PFT is the gold standard for the diagnosis of COPD. Small airway functional disease is detected when PFT shows small airway ventilation dysfunction. However, PFT provides little information about structural disease and is poorly related to respiratory symptoms. These ndings point to the lack of sensitivity of PFT in detecting small airway structural disease.
So it is necessary to develop novel metrics for the detection of early COPD. We hypothesized that the relationship between digital lung 3D imaging technology with small airway structural disease is utilized to diagnose early COPD.
Digital lung 3D imaging technology is a computer-aided diagnosis system, which is a means of assessment of airway disease. Miranda Kirby and Surya P. Bhatt proposed the following functions: 1) evaluate the lung function changes, 2) measure the pathological damages of COPD (peripheral airway stenosis, air ow limitation, etc), 3) reconstruct 3D lung structure, respiratory biphasic bronchial tree [14,15]. Digital lung 3D imaging technology has obvious advantages in early COPD screening. Therefore, we investigated small airway structural, functional changes and early COPD by combining digital lung 3D imaging technology with PFT, which has never been reported before.

Selection of parameters and analysis of results
Chronic in ammation of early COPD is mainly small airway disease, which is an airway with a lumen diameter of ≤ 2 mm, mainly including bronchioles and terminal bronchus. Yan Li et al reported that WT, TDR, WA%, LD, and LA values of generations 5 to 7 bronchus could effectively evaluate airway disease [16]. The study detected small airways structural disease by the respiratory biphasic generation 5 to 7 bronchi of these parameters. The generation 7 is about 2mm, which is close to the small airway. At the same time, RB1, LB1, RB10, and LB10 were equivalent to the overall evaluation of the entire lung, which would avoid the difference in respiratory motion.
Some studies reported that distal bronchial parameters were more closely related to small airway air ow limitation than the proximal bronchial in COPD patients [17]. Furthermore, WT and LAA950% were well-accepted indicators re ecting the pathological changes of COPD. Hogg JC et al reported that FEV1, FEV1%, FEV1/FVC prompted lung ventilation, small airway in ammation, and exudation in patients, which were closely related with air ow limitation [18]. In the study, compared with generation 5 bronchus, there were signi cant correlations between FEV1/FVC with generation 7 WT (r = -0.592; p < 0.01), which was consistent with the study by Yan Li et al [19]. Moreover, Guangqin Xia et al reported that MEF25-75, MEF25, MEF50, MEF75, PEF were consistent with small airway disease [20]. In the study, compared with generation 5, there were signi cant correlations between MEF50 with generation 7 WT (r = -0.607; p < 0.01), LA (r = 0.632; p < 0.01), and WA% (r = -0.643; p < 0.01). Our results showed that we could evaluate small airway disease by digital lung 3D imaging technology, and generation 7 bronchus was more effective in assessing small airway disease.
Vasilescu D et al proposed that PRM was a speci c density threshold, and a relatively stable indicator for evaluating small airway disease [21,22]. In this study, the digital lung 3D imaging technology parameters (%LAA950, PRM fsad et al) and PFT were correlated, which indicated that we could effectively evaluate small airway disease using the technology. In addition, Harvey BG and other studies had found that normal smokers with decreased DLCO also develop COPD, which was consistent with results of the study [23].

Assessing small airway functional and structural disease by PFT and digital lung 3D imaging technology in the observation group
Compared with the control group, there were signi cant differences between digital lung 3D imaging technology parameters and PFT in the observation group (P<0.05). Furthermore, the respiratory biphasic bronchial tree also showed small airway structural change. Our results showed that the observation group patients had structural and function disease by digital lung 3D imaging technology parameters and PFT, and would be diagnosed as early COPD. The study was an exploration of the diagnosis of early COPD. These functional and structural disease need inclusion in cohort studies of established COPD and early disease, to better understand their clinical relevance in COPD.

Limitations
The current study is not without limitations. Due to the high technical requirements and large data workload, the sample collection was still small. Moreover, we showed that small airway disease patients was compared with the normal. In the future, it will be compared with mild, moderate, severe, very severe COPD, for assessing small airway disease. We will continue to explore the study of early COPD and individualized treatment, and provide more evidence for slowing the progress of the disease.

Conclusion
Our results showed that we could use PFT and digital lung 3D imaging technology to detect small airway functional and structural disease that applied for screening early COPD.

Declarations
Ethics approval and consent to participate This study was approved by the ethics committee at the 903th Hospital of People Liberation Army and was performed in accordance with the ethical standards laid down in the Declaration of Helsinki. Written informed consent was obtained from each participant enrolled in the study.

Consent to publish
All individual materials such private images have been obtained the informed consent before published.

Availability of data and materials
The datasets and related materials within the above study can be available from the corresponding author on a reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors.
Authors' contributions QYC, HMT, CYJ designed and performed the whole study, discussed and analyzed the ndings, and wrote the paper. YQS, KF performed a part of the study, discussed and analyzed a part of the ndings, and helped write the paper. YKF, JS collected data and discussed the ndings. ZYZ helped analyze digital lung 3D imaging. All authors read and approved the nal manuscript. Tables   Table 1 Correlations between digital lung 3D imaging technology parameters and PFT Note: *P < 0.05, which is relevant; **P < 0.01, which is clearly correlated. Table 2 Comparisons of PFT and digital lung 3D imaging technology parameters between two groups   Figure 1 post-processing software segmentation of the respiratory biphasic bronchial tree (a-b), to obtain the measurement position of generations 5 to 7 bronchus (c-f).