Abstract
Background
Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished.
Objectives
The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation.
Methods
This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated.
Results
Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm<sup>2</sup>; SAT area (mean), 29.3 versus 36.8 cm<sup>2</sup>; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s.
Conclusions
The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.
Keywords: Chest computed tomography, Chronic obstructive pulmonary disease, Emphysema, Muscle wasting
Introduction
Smoking is a major cause of morbidity and mortality worldwide [1, 2]. Smoking causes damages to the lungs, leading to airflow limitation and a diagnosis of chronic obstructive pulmonary disease (COPD), and induces systemic inflammation, increasing risks of diseases outside the lungs [3, 4, 5]. However, not all smokers develop COPD, and the clinical manifestation is very heterogeneous in smokers [6]. A subgroup of smokers without airflow limitation also shows respiratory symptoms, poor quality of life, and impaired exercise capacity [7, 8]. Moreover, extrapulmonary abnormalities, such as cardiovascular disease and sarcopenia, can develop in smokers without COPD, and mortality is higher in non-COPD smokers with muscle wasting than those without muscle wasting [7, 9, 10]. Nonetheless, factors associated with the development of extrapulmonary abnormalities are less understood in smokers without COPD compared to those with COPD.
Emphysema is a main lung pathology of COPD [11] and is associated with extrapulmonary abnormalities, such as muscle wasting [12, 13, 14]. Emphysema is also observed in smokers without COPD and associated with poor prognosis in these smokers [15, 16]. Moreover, emphysema in smokers can be classified into subtypes, including centrilobular emphysema (CLE) and paraseptal emphysema (PSE) [11]. While the coexistence of CLE and PSE is common, CLE is more closely associated with small airway disease than PSE [17], and distinct associations of CLE and PSE with clinical and physiological outcomes have been increasingly recognized. These suggest that the associations of CLE and PSE with extrapulmonary abnormalities may be different.
Smokers with CLE (including COPD patients) experience exacerbations more frequently and show a lower level of blood-soluble receptor for advanced glycation end-products (sRAGE), which has anti-inflammatory properties, than those with PSE [18, 19, 20, 21]. Furthermore, CLE, but not PSE, is associated with coronary artery calcification (CAC) and osteoporosis in smokers with and without COPD [10, 22]. Since systemic inflammation causes muscle wasting and cardiovascular disease [3, 4], it was hypothesized that susceptibility to extrapulmonary abnormalities could be higher in smokers with CLE than in those without, irrespective of PSE, even when COPD is absent.
Chest computed tomography (CT) allows for localizing CLE and PSE in the lungs and evaluating extrapulmonary structures, including pectoralis muscles (PM), adjacent subcutaneous adipose tissue (SAT), erector spinae muscle (ESM), epicardial adipose tissue (EAT), bone mineral density (BMD), and CAC [12, 13, 14, 23, 24, 25, 26, 27]. Therefore, this study used lung cancer screening CT to test whether CLE could be associated with extrapulmonary CT findings independent of concomitant PSE in smokers without airflow limitation.
Materials and Methods
Study Design
This study retrospectively and consecutively enrolled current smokers aged ≥40 years old with a history of ≥10 pack-years who participated in a lung cancer screening program and underwent chest inspiratory CT and spirometry on the same day in Takeda Hospital and Tsukuba Medical Center Hospital in Japan. Smokers with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.7 or FEV1/FVC < lower limit of normal on spirometry were excluded. Further exclusion criteria were: 1) a history of lung resection; 2) abnormal CT findings extending to at least one lobe, such as tumors, consolidations, atelectasis, and thoracic deformities; and 3) lack of smoking status information. The study was conducted in accordance with the Declaration of Helsinki. The ethics committees of Kyoto University Hospital, Takeda Hospital, and Tsukuba Medical Center Hospital approved the study (approval R1660-3 and R2751) and made the decision to waive written informed consent due to the retrospective nature of the study.
Spirometry and Clinical Examination
Spirometry was performed using a Spiroshift SP-770 COPD (Fukuda Denshi, Tokyo, Japan) and an automated electronic spirometer SYSTEM 7 (Minato Medical Science, Osaka, Japan) by well-trained technicians following the statement of the American Thoracic Society/European Respiratory Society [28]. The reference values of FEV1 and FVC values were calculated based on the LMS method for the Japanese population [29]. Smoking status, history of weight gain >10 kg from age 20, and lifestyle behaviors, including physical activity sufficiency (moderate-intensity physical activity for ≥60 min/day), regular exercise habits (performing exercise ≥2 times/week), and fast walking habits (walking faster than the people of the same sex and nearly the same age), were evaluated using self-report questionnaires [30]. Waist circumference was measured by trained staff. Blood tests, including WBC (white blood cell count), CRP (C-reactive protein), total protein, and albumin, were performed. CRP was evaluated as a nominal variable, with a cut-off value of 0.1 mg/dL [31].
CT Acquisition
CT images of the whole lungs were obtained at full inspiration using 3 different scanners, including an Aquilion Prime scanner (Canon Medical Systems, Otawara, Japan) at Takeda Hospital and an Aquilion One scanner (Canon Medical Systems) and a LightSpeed VCT scanner (GE Healthcare, Waukesha, WI, USA) at Tsukuba Medical Center. In Takeda Hospital, archived images of 0.5 mm slices reconstructed with the sharp (FC53) kernel were converted to soft kernel (FC13)-based images at 1.0 mm slice thickness using a previously established deep neural network model [32]. In the Tsukuba Medical Center, images at 1.0 mm and 1.25 mm slice thicknesses reconstructed with the soft (FC02 and STANDARD) kernel and sharp (FC53 and LUNG) kernel were obtained using an Aquilion One and LightSpeed VCT scanner, respectively. The scanning conditions were 120 kVp, 0.4 s exposure time, and autoexposure control for all 3 scanners. The sharp kernel-based images were used for visual assessment of CLE and PSE, whereas the soft kernel-based images were used for quantifications of PM, SAT, ESM, EAT, and CAC.
CT Analyses of Emphysema
The Fleischner Society classification system [11] was used for visual assessment of CLE and PSE. The severity grade of CLE included trace, mild, moderate, confluent, and advanced destructive, while the severity grade of PSE included mild and substantial. CLE and PSE were considered present when at least trace CLE and mild PSE were identified, respectively. Each CT scan was assessed by two CT-experienced pulmonologists, and the discordances were adjudicated by a 15-year-experienced chest radiologist, as previously reported [33]. Additionally, in smokers whose CT scans were performed using the Aquilion Prime scanner (n = 213), emphysema in the entire lungs was quantitatively evaluated by measuring the volume percentage of low attenuation regions < −950 Hounsfield Unit (HU) to total lung volume (LAV%), as previously reported [26].
CT Analysis of Extrapulmonary Features
PM, SAT, ESM, EAT, and CAC were quantitatively evaluated using ImageJ (Fiji) software [34] for manual masking of target regions and custom-made Python scripts for automatic calculation of areas. On the first axial slice above the aortic arch, the left and right PM (major and minor) were manually segmented from regions with CT values ranging between −50 and +90 HU, as previously reported [12]. SAT was automatically identified as regions located between the PM and the skin surface on the same axial slice [25]. The left and right ESM were manually segmented on a single axial slice at the level of the lower margin of the 12th thoracic vertebra [13, 14]. EAT area at the origin of the left main coronary artery level, which was closely associated with the total volume of the entire EAT [35], was localized by manually tracing the pericardium and extracting areas with CT values between −230 and −30 HU. PM index, SAT index, ESM index, and EAT index were obtained by dividing the sum of the cross-sectional areas (centimeters squared) of PM, SAT, ESM, and EAT by the squared height (meters squared) to account for between-subject differences in body size as previously reported [9, 25]. To calculate BMD, the elliptical regions of interest (ROI) were placed on the body of the 4th, 7th, and 10th thoracic vertebrae at each mid-vertebral slice, and then mean CT values for the 3 ROIs were obtained and averaged as previously reported [23]. Finally, to evaluate CAC, the Agatston score was calculated. Areas of coronary calcium with CT density of ≥130 HU and ≥1 mm2 along the coronary artery were measured on each axial slice, multiplied by a weighting factor defined based on their maximal CT density, totaled, and standardized to minimize the effect of varying slice thickness [36, 37]. CAC was considered present when the Agatston score was >100 [38].
Statistical Analysis
Statistical analyses were performed using R statistical software, version 4.0.1 (R Foundation for Statistical Computing, Vienna, Austria). Data are expressed as the mean (standard deviation [SD]) unless otherwise indicated. Subjects' characteristics were compared using Fisher's exact test for categorical variables and the Student's t test for continuous variables. Multivariable linear regression models were constructed including age, sex, height, weight, smoking history (smoking duration and daily tobacco consumption), the presence of PSE, the presence of CLE, and CT scanners as independent variables and PM area, SAT area, or BMD as the dependent variable. The variables were chosen a priori based on a thorough review of the literature, which have shown associations between age, body size, smoking history, and FEV1 with skeletal muscle quantity and BMD [9, 12, 13, 23]. The CT scanners were included in the model because this study used different CT protocols (different scanners and reconstructions). Each variable was divided by its SD in a multivariable linear regression model. SAT area and SAT index were log2-transformed to approximate a normal distribution in univariable and multivariable analysis. A p value <0.05 was considered statistically significant.
Results
Subject Characteristics and Emphysema Prevalence
Of 505 consecutive current smokers who underwent spirometry and CT, 146 smokers were excluded because of smoking history of <10 pack-years or lack of smoking history, 36 smokers were excluded because of the presence of airflow limitation, and 13 smokers were excluded because of the other exclusion criteria. A total of 310 current smokers without airflow limitations were included. As shown in Figure 1, 83 (26.8%) smokers had any CT sign of CLE, and the prevalence of PSE was higher in smokers with CLE than in those without CLE (67.5% vs. 23.3%, p < 0.001). Table 1 compares clinical features between smokers with and without CLE. Body mass index, history of weight gain, and FEV1/FVC were lower, and daily tobacco consumption was higher in smokers with CLE than in those without CLE, while age, sex, height, weight, waist circumference, WBC, CRP, and lifestyle behaviors (physical activity sufficiency, regular exercise habits, and fast walking habits) did not differ between the two groups.
Fig. 1.
Prevalence of centrilobular emphysema (CLE) and paraseptal emphysema (PSE). a Evaluation of CLE. The bar graph illustrates the proportions of CLE classifications (trace: 16.1%, mild: 9.4%, moderate: 1.0%, advanced destructive: 0.3%). Moderate and advanced destructive emphysema were categorized as “severe”. b Evaluation of PSE. The proportion of PSE is depicted, divided by the presence of CLE.
Table 1.
Subjects' characteristics
| All subjects | CLE – | CLE + | |
|---|---|---|---|
| N | 310 | 227 | 83 |
| Sex, male, n (%) | 270 (87.1) | 193 (85.0) | 77 (92.8) |
| Age | 54.0 (8.7) | 52.9 (8.5) | 57.1 (8.7)** |
| Height, cm | 169.4 (7.3) | 169.0 (7.5) | 170.4 (6.6) |
| Weight, kg | 69.6 (12.3) | 70.1 (12.4) | 68.1 (12.0) |
| BMI | 24.2 (3.6) | 24.5 (3.6) | 23.3 (3.3)* |
| BMI <18.5, n (%) | 11 (3.5) | 6 (2.6) | 5 (6.0) |
| BMI ≥30, n (%) | 21 (6.8) | 15 (6.6) | 6 (7.2) |
| Waist circumference | 85.9 (9.9) | 86.4 (9.8) | 84.7 (9.9) |
| Smoking duration, ≥20 years, n (%) | 286 (92.3) | 210 (92.5) | 76 (91.6) |
| Daily tobacco consumption, ≥1 pack/day, n (%) | 155 (50.0) | 100 (44.1) | 55 (66.3)** |
| FEV1, L | 2.97 (0.61) | 3.00 (0.61) | 2.87 (0.58) |
| % predicted FEV1, % | 93.3 (12.7) | 93.8 (11.7) | 92.1 (14.5)* |
| FVC, L | 3.73 (0.74) | 3.74 (0.73) | 3.71 (0.76) |
| % predicted FVC, % | 93.4 (12.5) | 94.36 (12.2) | 90.3 (13.7) |
| FEV1/FVC | 0.80 (0.05) | 0.80 (0.05) | 0.77 (0.05)** |
| PSE, n (%) | 109 (35.2) | 53 (23.3) | 56 (67.5)** |
| Fast walking habit, n (%) | 150 (48.7) | 114 (50.4) | 36 (43.9) |
| Regular exercise habit ≥30 min/day, n (%) | 75 (24.4) | 58 (25.7) | 17 (20.7) |
| Physical activity sufficiency ≥60 min/day, n (%) | 103 (33.4) | 74 (32.7) | 29 (35.4) |
| Weight gain +10 kg, n (%) | 163 (52.9) | 128 (56.6) | 35 (42.7)* |
| WBC, /mm3 | 6,419 (1,867) | 6,356 (1,792) | 6,592 (2,058) |
| CRP ≥0.1 mg/dL, n (%) | 96 (31.0) | 64 (28.2) | 32 (38.6) |
| Total protein, g/dL | 7.03 (0.38) | 7.06 (0.35) | 6.94 (0.43)* |
| Albumin, g/dL | 4.4 (0.3) | 4.4 (0.3) | 4.3 (0.3)* |
Data are expressed as the mean (SD) and n (%). BMI, body mass index; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; CLE, centrilobular emphysema; PSE, paraseptal emphysema; WBC, white blood cell count; CRP, C-reactive protein.
p < 0.05
p < 0.01 (compared to smokers without CLE).
Comparisons between Smokers with and without CLE
Figure 2 shows that PM area, SAT area, and BMD were significantly lower in smokers with CLE than in those without (PM area (cm2), mean (SD) = 34.5 (8.5) versus 38.6 (10.1), p < 0.01; SAT area (cm2), mean (SD) = 29.3 (12.0) versus 36.8 (17.3), p < 0.001; BMD (HU), mean (SD) = 158.3 (45.8) versus 178.4 (38.6), p < 0.001), while ESM area, EAT area, and the prevalence of CAC did not differ between the two groups. The result was consistent when PM index and SAT index were used instead of PM and SAT areas. Table 2 shows the results of univariable and multivariable analyses to explore associations of CLE, PSE, and FEV1 with PM, SAT, and BMD. In multivariable models, the presence of CLE was associated with lower PM area (β (95% confidence interval, 95% CI) = −0.35 (−0.56, −0.14)) after adjusting for the presence of PSE, age, sex, height, weight, smoking history, and FEV1. In contrast, the presence of CLE was not associated with SAT area (β (95% CI) = −0.09 (−0.25, 0.06)) or BMD (β (95% CI) = −0.22 (−0.48, 0.04)) after adjusting for the same variables as used in the model for PM. Furthermore, in subanalyses of smokers whose CT was obtained using the same scanner (n = 213), as shown in online supplementary Table S1 (for all online suppl. material, see www.karger.com/doi/10.1159/000529031), there was no significant difference in LAV% between smokers without CLE (n = 51) and those with CLE (n = 162) (LAV%, mean (SD) = 1.40 (1.84) versus 2.06 (2.81) %). Online supplementary Table S2 shows that the association of CLE with lower PM area was still detected (β (95% CI) = −0.46 (−0.70, −0.22)) in a multivariable model after adjusting for a combination of the same variables and LAV%.
Fig. 2.
Comparisons of extrapulmonary CT measures between smokers with and without centrilobular emphysema (CLE). a Illustration of extrapulmonary structures, including the pectoralis muscles (PM, red), subcutaneous adipose tissue adjacent to the PM (SAT, blue), erector spinae muscles (ESM, green), and epicardial adipose tissue (EAT, magenta), coronary artery calcification (CAC, yellow), and bone marrow density (BMD, cyan) on chest CT. b PM area and SAT area were significantly lower in smokers with CLE than in those without CLE. In statistical analyses, SAT was log2-transformed. c BMD was significantly lower in smokers with CLE than in those without CLE. d The rate of CAC did not differ between smokers with and without CLE. e Height-adjusted cross-sectional areas of PM, SAT, ESM, and EAT (PM index, SAT index, ESM index, and EAT index) were also compared between smokers with and without CLE. In statistical analyses, SAT index was log2-transformed. * indicates p < 0.05 compared to smokers without CLE.
Table 2.
Univariable and multivariable linear regression analysis for PM, SAT index, and BMD
| Models for PM area | Models for SAT area | Model for BMD | |
|---|---|---|---|
| Univariable analyses | |||
| CLE | –0.39** (–0.64, –0.14) | –0.52** (–0.77, –0.28) | –0.48** (–0.73, –0.24) |
| PSE | 0.01 (–0.23, 0.24) | –0.58** (–0.81, –0.36) | –0.23* (–0.47, 0.00) |
| FEV1 | 0.42** (0.32, 0.52) | –0.10 (–0.21, 0.01) | 0.24** (0.13, 0.35) |
| Multivariable analysesa | |||
| CLE | –0.35** (–0.56, –0.14) | –0.09 (–0.25, 0.06) | –0.22 (–0.48, 0.04) |
| PSE | 0.14 (–0.05, 0.33) | –0.12 (–0.27, 0.02) | 0.00 (–0.24, 0.24) |
| FEV1 | 0.11 (–0.02, 0.25) | 0.04 (–0.06, 0.14) | 0.10 (–0.06, 0.27) |
Univariable and multivariable models (n = 310) were constructed to explore factors associated with pectoralis muscle (PM) area, subcutaneous adipose tissue (SAT) area, and bone marrow density (BMD). Values are expressed as standardized estimates (95% confidence interval).
p < 0.05.
p < 0.01.
All multivariable models (n = 310) simultaneously included centrilobular emphysema (CLE), paraseptal emphysema (PSE), forced expiratory volume in 1 s (FEV1), and basic demographic factors, including age, sex, height, weight, smoking history (duration ≥20 years and daily consumption ≥1 pack/day), and CT scanner, as independent variables. SAT area was log2-transformed to approximate a normal distribution.
Discussion
This study used the established visual emphysema subtyping system and showed that the presence of CLE was associated with lower PM area independent of the presence of PSE, age, sex, height, weight, smoking history, and FEV1 in smokers without airflow limitation. Although previous reports have shown the associations between overall emphysema severity and skeletal muscle loss in smokers both with and without COPD [9, 13, 30], this study is the first to show that the presence of CLE, rather than PSE, is closely associated with skeletal muscle loss in non-COPD smokers.
There is growing evidence that respiratory symptoms and CT finding of emphysema are associated with worsening quality of life and exercise capacity, increased exacerbation frequency, and poor outcomes in smokers without airflow limitation and COPD [8, 15, 16]. Following a study by McDonald et al. who showed the association between lower PM area and morbidity in smokers with COPD [12], Diaz et al. showed that PM area is associated with overall emphysema and mortality in current smokers without airflow limitation [9]. Moreover, Mason et al. recently showed that longitudinal loss of PM area is also associated with mortality in smokers with and without COPD [27]. The present data extend those previous findings by showing that CLE, but not PSE, is associated with lower PM area in smokers without COPD. Together with those previous findings, we think that CLE could be an imaging marker for non-COPD smokers at a high risk for muscle wasting and mortality. Further studies are needed to test whether, in addition to smoking cessation, any interventions including inhaler therapy and pulmonary rehabilitation can be effective to improve outcomes of these smokers.
The associations among cigarette smoking, sarcopenia, and molecular pathways of skeletal muscle breakdown are increasingly being uncovered [39, 40]. Although this study did not find a difference in WBC or CRP between smokers with and without CLE, we speculate that inflammation might be a factor linking CLE to skeletal muscle loss, detected as low PM, based on the following previous data. First, emphysema severity in smokers is associated with systemic inflammation [41], and emphysema in smokers is generally CLE dominant. Second, pathological studies have confirmed greater airway inflammation and protease activity in CLE compared to other emphysema subtypes [42, 43]. This local enhancement of airway inflammation might spill over into the systemic circulation. Third, a previous finding of lower blood sRAGE in patients with CLE than in those with PSE [21] suggests a higher systemic inflammation in those with CLE.
The multivariable models showed that, unlike CLE, PSE was not associated with lower PM index. It is possible that the influence of CLE on the extrapulmonary manifestations in smokers is greater than that of PSE. Moreover, the present finding of lower PM index in non-COPD smokers with CLE suggests that skeletal muscle loss might precede the development of COPD in smokers. This association should be investigated in future longitudinal studies of smokers by observing changes in PM index and blood biomarkers of systemic inflammation in relation to pulmonary function.
The subanalysis including subjects evaluated by the same CT scanner showed that the association between CLE and PM index was independent of LAV%. This finding suggests that visual assessment may complement quantitative emphysema measurements, particularly in smokers without airflow limitation [16].
The assessments of fast-walking habits, regular exercise habits, and physical activity sufficiency did not differ between smokers with and without CLE. Although previous studies have suggested that such behavioral and demographic factors are associated with skeletal muscle loss and sarcopenia in the general population [44] and in patients with COPD [45], these findings suggest that walking and exercise habits and the extent of physical activity could not affect the present finding of an association between CLE and lower PM index.
Unlike PM index, ESM index did not differ between smokers with and without CLE. Studies of patients with COPD have shown that ESM is associated with emphysema severity and worse prognoses more closely than PM [13, 14], whereas studies of smokers without airflow limitation have shown that PM is associated with emphysema severity more closely than ESM [9]. It is possible that antigravity muscles, including ESM, are affected not only by systemic inflammation but also by decreased physical activity, which is more frequently observed in smokers with COPD than in those without COPD [13, 14]. Therefore, we speculate that PM might be more sensitive to damage by systemic inflammation caused by cigarette smoking than ESM.
The presence of CLE was not associated with CAC. Moreover, CLE was associated with lower BMD in univariable analyses, but this association disappeared in the multivariate analysis. These findings are inconsistent with previous reports showing that CLE was associated with higher CAC incidence [22] and lower BMD [10] in smokers with and without COPD. Because the prevalence of CLE and the extent of CAC are greater and BMD is lower in smokers with COPD than in those without COPD [24, 33, 46, 47], we speculate that these inconsistent results might be because this study included only smokers without airflow limitation.
There are several limitations to this study. First, this study enrolled smokers who participated in a lung cancer screening program. The applicability of the present findings to the general population should be cautiously considered. Second, this study was cross-sectional, and the direction of cause and effect when interpreting the association between CLE and PM is unclear. Third, the presence/absence of airflow limitation was determined using prebronchodilator spirometry because postbronchodilator spirometry is not routinely performed in the lung cancer screening program. Lastly, our population is predominantly male. This might reflect sex difference in smoking rates in the general Japanese population (male 27.1%, female 7.5%) [48]. The generalizability of the present findings to females needs to be examined further.
Conclusion
The present data demonstrated the independent association of CLE and a smaller size of the PM in current smokers without airflow limitation. Therefore, susceptibility to skeletal muscle loss could be high in smokers with CLE, even when COPD is absent. Further studies are warranted to investigate whether the visual CT sign of CLE is associated with the future development of muscle wasting and sarcopenia in non-COPD smokers.
Statement of Ethics
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (approval numbers R1660-3 and R2751), the Ethics Committee of Takeda Hospital (approval number 2019), and the Ethics Committee of Tsukuba Medical Center Hospital (approval number 2021-018). Written consent was waived due to the retrospective nature of the study by the decision of the ethics committees above.
Conflict of Interest Statement
Naoya Tanabe, Susumu Sato, Tsuyoshi Oguma, and Toyohiro Hirai were supported by a grant from FUJIFILM Co., Ltd. Susumu Sato received grants from Nippon Boehringer Ingelheim, Philips Respironics, Fukuda Denshi, Fukuda Lifetec Keiji, and ResMed outside of the submitted work. None of these companies played a role in the design or analysis of the study or in the writing of the manuscript. The other authors have no conflicts of interest to declare.
Funding Sources
The study was partially supported by a grant from the Japan Society for the Promotion of Science (JSPS) (Grants-in-Aid for Scientific Research 19K08624).
Author Contributions
Tomoki Maetani, Naoya Tanabe, Yusuke Shiraishi, Satoru Terada, Hiroshi Shima, Tsuyoshi Oguma, Susumu Sato, and Toyohiro Hirai were involved in the study design and data interpretation. Tomoki Maetani, Naoya Tanabe, Yusuke Shiraishi, Takafumi Shimada, Satoru Terada, Fumi Mochizuki, Ryo Sakamoto, Shizuo Kaji, Hiroaki Iijima, and Izuru Masuda were involved in the data collection. All of the authors critically revised the report, commented on drafts of the manuscript, and approved the final report.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Supplementary Material
Supplementary data
Funding Statement
The study was partially supported by a grant from the Japan Society for the Promotion of Science (JSPS) (Grants-in-Aid for Scientific Research 19K08624).
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Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.