Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features.

BACKGROUND: Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features. However, there have been few reports on the structural lung abnormalities found in this patient population. Multi-detector computed tomography (MDCT) can detect emphysematous low-attenuation areas (LAA) within the lung, airway thickness (wall area percentage, WA%), and the loss of pulmonary vasculature as the percentage of small pulmonary vessels with cross-sectional area (CSA) less than 5 mm2 (%CSA<5). We analyzed differences in structural lung changes over time between patients with COPD and those with COPD with asthma-like features using these CT parameters.
MATERIAL AND METHODS: We performed pulmonary function tests (PFTs), MDCT, and a COPD assessment test (CAT) in 50 patients with COPD and 29 patients with COPD with asthma-like features at the time of enrollment and two years later. We analyzed changes in clinical parameters and CT indices over time and evaluated differences in structural changes between groups.
RESULTS: The CAT score and FEV1 did not significantly change during the follow-up period in either group. Emphysematous LAA regions significantly increased in both groups. The %CSA<5 showed a small but significant increase in COPD patients, but a significant decrease in patients with COPD with asthma-like features. The WA% at the distal bronchi was significantly decreased in COPD, but did not significantly change in COPD with asthma -like features.
CONCLUSION: Emphysematous LAA increased in patients with COPD with and without asthma-like features. The %CSA<5 and WA% at the distal bronchi did not change in parallel with LAA. Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Patients with COPD with asthma-like features may have different longitudinal structural changes than those seen in COPD patients.

Background

Chronic obstructive pulmonary disease (COPD), a common disease that is increasing in prevalence, is characterized by persistent respiratory symptoms and chronic airflow limitation [1]. Worldwide, COPD is the third leading cause of death, and mortality continues to rise [2]. The chronic airflow limitation in COPD is caused by a mixture of small airway disease and parenchymal destruction, which leads to multiple COPD phenotypes. For example, the classical phenotype is emphysema/chronic bronchitis, and other phenotypes are frequent-exacerbator/non-exacerbator [3, 4]. Recently, “asthma- COPD overlap” (ACO) has been recognized in clinical practice. A joint project of the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published a consensus on ACO [5]. The prevalence of ACO has been reported to be between 13% and 55% [6]. It has not been defined definitively, and previous studies have used multiple different diagnostic criteria. The asthmatic components for the diagnosis of ACO include history of asthma; asthma-like symptoms, positive bronchodilator test, blood eosinophilia, high total IgE, and/or atopy etc. [6-8]. GINA/GOLD applies a stepwise approach for the diagnosis of ACO, in which each characteristic of COPD and asthma are assessed. However, some patients with COPD have asthma-like features [9], even if they are not diagnosed as ACO. COPD with asthma-like features is a clinical phenotype of COPD and this phenotype is associated to individualized treatment [9-11].

Recently, multi-detector computed tomography (MDCT) has been used to evaluate structural changes in the lung. The loss of lung tissue associated with emphysema is detected as low-attenuation areas (LAA) on CT scans [12]. LAA percentage (LAA%) in patients with COPD is higher than in normal subjects [13], and correlates with COPD mortality independently of pulmonary function tests [14]. Airway wall thickening can also be measured using CT. Nakano et al. found that wall thickening in the apical bronchus of the right upper lobe correlated significantly with FEV1 in patients with COPD [15]. The inner luminal area (Ai) and the wall thickness (wall area percentage, WA%) were measured at the third- to the sixth-generation airways. These indices correlated significantly with airflow limitation, and such correlations were more closely related to the distal than the proximal airways [16]. Moreover, chronic respiratory symptoms were positively associated with WA% in airways with a luminal diameter between 5 and 10 mm [17]. Recently, several studies have used a novel CT marker to evaluate the area of small pulmonary vessels, the percentage of small pulmonary vessels (%CSA). The %CSA<5 reflects pulmonary vascular alteration and correlates with airflow limitation, the extent of emphysema, and pulmonary hypertension in patients with COPD [18, 19].

Although there are many longitudinal studies on health status and lung function in COPD [20], longitudinal structural changes in COPD with asthma-like features have not been fully investigated. Several studies have been performed in patients with emphysema [21, 22], but there are few reports on changes in airway [23] or vascular remodeling [24]. The structural characteristics of ACO and COPD are different. Hardin et al. reported that patients with ACO had less emphysema and greater airway wall thickness compared to patients with COPD [25]. We previously examined longitudinal structural changes in COPD patients and found that WA% at the distal bronchi and %CSA<5 did not change in parallel with LAA [26]. However, differences in longitudinal structural changes between the patients with COPD versus those with COPD with asthma-like features have not been fully elucidated.

The recognition of COPD with asthma-like features by the assessment of their structural characteristics may provide essential information for individualized management of patients with COPD. The present study aimed to investigate the longitudinal structural changes in patients with COPD with asthma-like features using MDCT. Such changes include changes in pulmonary emphysema, airway disease, and pulmonary vascular alteration. This study also aimed to evaluate the differences in structural abnormalities between COPD patients and patients with COPD with asthma-like features.

Materials and methods

Subjects

This prospective observational study enrolled 137 patients who presented to Chiba University Hospital from June 2010 to August 2016 for management of COPD. Patients were excluded if they had abnormal lung parenchymal lesions other than emphysematous change. At enrollment, 10 patients were excluded for the following reasons: 4 interstitial pneumonia, 1 infectious pneumonia, 1 old pulmonary tuberculosis, and 4 lung cancer or nodules. At the follow up period, 15 patients were excluded: 6 interstitial pneumonia, 2 infectious pneumonia, 3 lung cancer or nodules, 2 cardiac failure, and 2 pleural effusion. Finally, 50 patients with COPD and 29 patients with COPD with asthma-like features were enrolled in the study (Fig 1). The diagnosis of COPD was based on chronic respiratory symptoms, with smoking history, physical examination and results of spirometry according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommendations [27]. Pulmonary function tests (PFTs) were performed with a Fudac-60 (Fukuda Denshi; Tokyo, Japan). Spirometric measurements included forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1), which were expressed as their predicted values based on the Japanese Respiratory Society (JRS) guidelines [28].

Fig 1

Flow chart of the study participants.

In this study, patients with COPD who experienced asthma symptoms (episodes of breathlessness, wheezing, cough, and chest tightness that were worse at night or in the early morning), bronchodilator reversibility (improvement greater than or equal to 200ml and 12% increase in FEV1 compared to pre-bronchodilator data), blood eosinophils >5% or 300/ml, high levels of serum IgE, and/or history of allergic rhinitis were diagnosed with COPD with asthma-like features, in accordance with GINA and GOLD guidelines [5].

Patients underwent a COPD assessment test (CAT), PFTs and MDCT at the time of enrollment and two years later. Exacerbations were defined as a deterioration of respiratory symptoms that required antibiotics, systemic steroids and/or hospital admission [22].

The Ethics Committee of the Chiba University School of Medicine approved the study protocol (approval number: 857). Written informed consent was obtained from all study participants.

MDCT scanning

All patients were scanned with a 64-MDCT scanner (Aquillion ONE, Toshiba Medical Systems; Tokyo, Japan) from the thoracic inlet to the diaphragm while at full inspiration. None received contrast medium. The scan was carried out with the following settings: 0.5-mm collimation; 120kV; auto-exposure control; gantry rotation time of 0.5 seconds; and beam pitch of 0.83. All images were reconstructed using standard reconstruction algorithms with a slice thickness of 0.5 mm and a reconstruction interval of 0.5 mm. The voxel size was 0.63×0.63×0.5 mm.

MDCT measurements

For the measurements of LAA and CSA, we selected three CT slices, which were taken at 1 cm above the upper margin of the aortic arch (upper lung fields), 1 cm below the carina (middle lung fields), and 1 cm below the right inferior pulmonary vein (lower lung fields) [18]. These CT images were analyzed using ImageJ software, Version 1.44 (imagej.nih.gov/ij/download/).

LAA measurements were conducted as follows: The threshold technique for the total lung area (TLA) was adopted between -500 and -1024 Hounsfield units (HU). Since LAA was detected with an attenuation of -950 HU, images were converted into binary images with a window level of -950 HU. The range of circularity was set from 0 to infinity. With these settings, the LAA was automatically calculated. The LAAs of each lung field were summed, and the average of these values was determined.

CSA measurements were conducted as follows: The threshold technique for the total lung field was adopted between -500 and -1024 HU. Segmented images were converted into binary images with a window level of -720 HU. The range of circularity was set from 0.9 to 1.0 using the "analyze particles" function of the ImageJ software. With these settings, the CSA was measured separately by the size of each vessel (less than 5 mm2; CSA<5). The CSAs of each lung field were summed, and the average of these values was determined. The percentage of CSA<5 (%CSA<5), and LAA (%LAA) in the TLA were calculated.

We used the free open-source software Airway Inspector (Brigham and Women’s Hospital) for the measurements of WA%. WA% measurements were conducted according to the method of Yamashiro et al. [29]. We identified the third and fifth generations of the B1 and B10 bronchi in the right lung. The measured point was peripherally next to the branching points in each generation. Ai and the outer area of the bronchus (Ao) were measured semiautomatically with the full-width at half-maximum method of the software. The WA% was defined with the equation WA% = 100 (Ao—Ai) / Ao. The MDCT measurements were evaluated independently by two pulmonologists (RA and YM). All data were anonymized and the observers were blinded to other characteristics of the subjects when the imaging analyses were performed.

Statistical analysis

JMP 13.0 software was used for all statistical analyses (SAS Institute, Cary, NC), with the results expressed as mean (± SD) unless otherwise indicated. Comparisons of longitudinal changes in CT parameters, PFTs, and CAT scores between enrollment and follow-up in each group were performed using the Wilcoxon signed-rank test. Comparisons were performed with a chi-square test for categorical variables. Differences in the data between the patients with COPD and COPD with asthma-like features were performed with the Mann-Whitney U test. For all statistical analyses, the level of significance was set at p <0.05.

Results

Patient characteristics

The clinical characteristics of the patients are presented in Table 1. There were 50 patients with COPD (44 men and 6 women; mean age, 70.1 ± 6.9 years) and 29 patients with COPD with asthma-like features (23 men and 6 women; mean age, 67.9 ± 8.5 years). There were no differences between the two groups in age, sex, percentage of ex/current smokers, smoking history or body mass index. All of the patients with COPD with asthma-like features met the criteria for asthma symptoms, whereas 9 (31%) had bronchodilator reversibility, 17 (59%) had blood eosinophilia, 13 (45%) had high levels of serum IgE, and 2 (7%) had a history of allergic rhinitis. The number of patients in each GOLD stage were as follows: COPD group: stage I, n = 13 (26%); stage II, n = 27 (54%); stage III, n = 7 (14%); stage IV, n = 3 (6%); COPD with asthma- like features group: stage I, n = 3 (10.3%); stage II, n = 12 (41.4%); stage III, n = 11 (38%); stage IV, n = 3 (10.3%). The COPD with asthma-like features group contained more patients with severe GOLD stage disease (P = 0.048), and the frequency of exacerbation tended to be higher in the group with COPD with asthma-like features (COPD vs asthma-like features: 1.4 ± 1.0 vs 3.1 ± 3.8, P = 0.0617). Additionally, the number of patients who received COPD treatment at enrollment and two years later was higher in the COPD with asthma-like features group (COPD vs asthma-like features: at enrollment 30% vs 89.7%, P < 0.0001, 2 years later 64.0% vs 96.6%, P = 0.0003).

Table 1

Characteristics of patients with COPD with and without asthma-like features.

	COPDMean (±SD)n = 50	COPD with asthma-like featuresMean (±SD)n = 29	P value(between groups)
Age (years)	70.1 ± 6.9	67.9 ± 8.5	NS
Sex (male/female)	44 (88%) / 6 (12%)	23 (79.3%) / 6 (20.7%)	NS
Ex-smokers/Current smokers	40 (80%) / 10 (20%)	27 (93.1%) / 2 (6.9%)	NS
Smoking history (pack-years)	56.0 ± 30.7	57.8 ± 44.5	NS
BMI (kg/m2)	23.8 ± 3.0	22.7 ± 3.4	NS
GOLD classification(I/II/III/IV)	13 (26%) / 27 (54%) / 7 (14%) / 3 (6%)	3 (10.3%) / 12 (41.4%) / 11 (38.0%) / 3 (10.3%)	0.048
Exacerbations (+/-)	12 (24%) / 38 (76%)	9 (31.0%) / 20 (69.0%)	NS
Exacerbations per 1 year	0.8 ± 0.5	1.6 ± 1.9	NS
COPD Treatment (Yes/No)at enrollment	15 (30%) / 35 (70%)	26 (89.7%) / 3 (10.3%)	< 0.0001
LAMA	15 (30%)	16 (55.2%)
LABA	1 (2%)	8 (27.6%)
ICS	0 (0%)	1 (3.4%)
ICS/LABA	4 (8%)	14 (48.3%)
LAMA/LABA	0 (0%)	2 (6.9%)
COPD Treatment (Yes/No) after 2 years	32 (64%) / 18 (36%)	28 (96.6%) / 1 (3.4%)	0.0003
LAMA	27 (54%)	20 (69.0%)
LABA	8 (16%)	6 (20.7%)
ICS	0 (0%)	7 (24.1%)
ICS/LABA	13 (26%)	14 (48.3%)
LAMA/LABA	0 (0%)	3 (10.3%)

BMI, body mass index; LAMA, long-acting muscarinic antagonist; LABA, long-acting β-agonist; ICS, inhaled corticosteroids; SD, standard deviation; NS, not significant

CAT score and PFTs

The CAT score, FEV1, and FEV1%predicted did not significantly change during the follow-up period in either group (Tables 2 and 3).

Table 2

Longitudinal changes in CAT score, PFTs, and CT measurements.

	COPDBaselineMean (±SD)	2-Year Follow-upMean (±SD)	P value(within group)	COPD with asthma-likefeaturesBaselineMean (±SD)	2-Year Follow-upMean (±SD)	P value(within group)
CAT score	8.7 ± 6.5	8.6 ± 7.1	NS	9.4 ± 7.0	10.6 ± 7.4	NS
FVC (L)	3.15 ± 0.72	3.19 ± 0.77	NS	3.01 ± 0.91	2.96 ± 0.86	NS
FEV1 (L)	1.83 ± 0.61	1.81 ± 0.62	NS	1.45 ± 0.55	1.41 ± 0.56	NS
FEV1/FVC (%)	57.5 ± 11.8	55.9 ± 11.5	0.0381	48.2 ± 11.0	47.5 ± 11.7	NS
FEV1% predicted (%)	67.9 ± 19.8	69.0 ± 21.3	NS	53.6 ± 17.7	53.9 ± 19.3	NS
V50/V25	3.7 ± 1.2	4.1 ± 1.6	0.0217	3.3 ± 1.3	3.3 ± 1.5	NS
TLA (mm2)	22272 ± 3091	22131 ± 3277	NS	22841 ± 4620	22823 ± 4824	NS
LAA (mm2)	1648 ± 2709	2144 ± 3100	< 0.0001	2787 ± 3606	3626 ± 4139	< 0.0001
LAA% (%)	6.8 ± 10.4	8.8 ± 11.7	< 0.0001	10.8 ± 13.0	14.1 ± 14.6	< 0.0001
CSA<5 (mm2)	157.0 ± 34.2	168.9 ± 39.7	0.0047	164.2 ± 33.4	147.7 ± 27.1	0.0034
%CSA<5 (%)	0.72 ± 0.19	0.78 ± 0.21	0.0074	0.77 ± 0.22	0.70 ± 0.21	0.0148
B1 WA%
Third	72.5 ± 7.2	72.0 ± 6.4	NS	71.0 ± 6.6	70.9 ± 9.0	NS
Fifth	83.9 ± 4.7	83.0 ± 4.6	NS	84.9 ± 4.1	83.6 ± 7.1	NS
B10 WA%
Third	71.4 ± 7.0	69.6 ± 6.7	NS	70.7 ± 7.5	71.1 ± 6.8	NS
Fifth	83.8 ± 3.8	80.9 ± 6.2	0.0004	82.8 ± 4.8	82.5 ± 4.7	NS
Mean WA%
Third	72.2 ± 6.1	70.9 ± 4.8	NS	70.9 ± 5.6	71.2 ± 6.5	NS
Fifth	83.9 ± 3.2	82.0 ± 4.6	0.0043	83.9 ± 3.5	83.2 ± 4.0	NS

CAT score, COPD assessment test score; PFTs, pulmonary function tests; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; V50/V25, forced expiratory flow at 50% vital capacity and forced expiratory flow at 25% vital capacity; TLA, total lung area; LAA, low-attenuation area; CSA<5, the cross-sectional area of pulmonary vessels <5 mm2; WA%, wall area percentage; SD, standard deviation; NS, not significant

Table 3

Annual changes in CAT score, PFTs, and CT measurements: Intra- and inter-group comparisons between patients with COPD with and without asthma-like features.

	COPD		COPD with asthma-like features		P value(between groups)
	Value	P value(within group)	Value	P value(within group)
CAT score	-0.1 ± 3.0	NS	0.3 ± 1.8	NS	NS
FEV1 (L)	-0.01 ± 0.11	NS	-0.02 ± 0.08	NS	NS
FEV1% predicted (%)	0.010 ± 0.086	NS	-0.001 ± 0.054	NS	NS
LAA% (%)	0.83 ± 1.72	< 0.0001	0.40 ± 0.53	< 0.0001	NS
%CSA<5 (%)	0.051 ± 0.104	0.0074	-0.035 ± 0.094	0.0148	0.0007
Mean WA% (%)
Third	-0.007 ± 0.037	NS	0.002 ± 0.027	NS	NS
Fifth	-0.011 ± 0.025	0.0043	-0.004 ± 0.021	NS	NS

CAT score, COPD assessment test score; PFTs, pulmonary function tests; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; LAA, low-attenuation area; CSA<5, cross-sectional area of pulmonary vessels <5 mm2; WA%, wall area percentage; NS, not significant.

The data are expressed as mean ± standard deviation.

The difference in CAT score was calculated by subtracting the value measured after 2 years from that measured at enrollment.

The difference in FEV1 (L) was calculated by subtracting the value measured after 2 years from that measured at enrollment.

The difference in FEV1% predicted (%) and the CT parameters (%) were calculated as follows: subtraction of the value measured after 2 years from that measured at enrollment, divided by the value at enrollment.

CT parameters

The CT parameters measured at enrollment and follow-up CT scans are shown in Table 2, while the annual changes in CT measurements are shown in Table 3. Fig 2 shows the changes in radiological parameters over two years of follow- up. There was no significant difference in all the CT parameters including LAA%, CSA<5, and WA% at enrollment between the two groups. LAA and LAA% significantly increased in both groups during the follow-up period (COPD: baseline vs two years later: 6.8 ± 10.4% vs 8.8 ± 11.7%, P < 0.0001. COPD with asthma-like features: baseline vs two years later: 10.8 ± 13.0% vs 14.1 ± 14.6%, P < 0.0001). TLA did not significantly change. The CSA<5 and %CSA<5 slightly but significantly increased in the COPD group (baseline vs two years later: 0.72 ± 0.19% vs 0.78 ± 0.21%, P = 0.0074). In contrast, the CSA<5 and %CSA<5 significantly decreased in the COPD with asthma-like features group (baseline vs two years later: 0.77 ± 0.22% vs 0.70 ± 0.21%, P = 0.0148). The annual changes in %CSA<5 were significantly different between the two groups (COPD vs asthma-like features: 0.051 ± 0.104 vs -0.035 ± 0.094, P = 0.0007).On the other hand, the mean WA% at the distal bronchi significantly decreased in the COPD group (baseline vs two years later: 83.9 ± 3.2% vs 82.0 ± 4.6%, P = 0.0043), while the WA% in the COPD with asthma-like features group did not significantly change during the follow-up period (baseline vs two years later: 83.9 ± 3.5% vs 83.2 ± 4.0%, not significant). The annual changes in mean fifth WA% were not significantly different between the two groups (COPD vs asthma-like features: -0.011 ± 0.025 vs -0.004 ± 0.021, P = 0.1352).

Fig 2

Changes in radiological parameters over two years of follow-up.

Notes: Radiological parameters were compared between enrollment and two-year follow-up with the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi. The thick horizontal bars at the sides of each graph show the median, while the thin horizontal bars at the sides of each graph show the interquartile range. Abbreviations: ALF, asthma-like features; LAA, low-attenuation area; CSA<5, the cross-sectional area of pulmonary vessels < 5 mm2; WA%, wall area percentage; NS, not significant.

Discussion

This is the first report of longitudinal morphological changes, including parameters of emphysema, airway wall thickness, and vascularity, in COPD with asthma-like features. The key findings of our study were as follows. First, emphysematous features (LAA%) significantly increased in both groups. Second, longitudinal changes in the percentage of small pulmonary vessels (%CSA<5) differed between COPD with asthma-like features and COPD alone. Among patients with COPD with asthma-like features, %CSA<5 significantly decreased during the two years of follow-up. In contrast, %CSA<5 significantly increased in patients with COPD alone. Third, we observed a slight but significant decrease in WA% in patients with COPD alone, although there was no significant change in WA% in patients with COPD with asthma-like features during the study period.

LAA% is recognized as an index of the extent of emphysema [12]. Emphysema is the main pathological lesion in COPD and is usually caused by tobacco smoke [1]. It is well known that LAA% gradually increases over time in COPD patients [30]. Patients with ACO have less severe emphysema than patients with COPD alone [25, 31]. Although there are a few reports on the cross-sectional structural characteristics of ACO [8, 32], longitudinal emphysematous changes in ACO have not been reported. Our findings suggest that emphysema progresses similarly in patients with COPD and those with COPD with asthma-like features. In COPD, exposure to tobacco smoke leads to chronic airway inflammation through the activation of inflammatory cells [33]. Regardless of smoking cessation, chronic inflammation persists [34] and causes emphysema progression [21]. In our study, most patients were past smokers, and all had a significant smoking history. Therefore, our data indicates that emphysematous destruction may progress in both patients with COPD and those with COPD with asthma-like features due to the fact that airway inflammation persist even after smoking cessation.

Another novel finding of this study was that changes in %CSA<5 differed between patients with COPD alone and those with asthma-like features. The %CSA<5 is a novel CT marker for microvascular alteration, and it is negatively correlated with the extent of emphysema and airflow limitation in COPD [18]. However, Saruya et al. reported that the progression of emphysema and pulmonary vascular alteration do not always occur in parallel. They found that, although emphysema might progress, the %CSA<5 might not always decrease, and the change in decrease was associated with various patient improvements, such as smoking cessation, decreased exacerbation risk, and appropriate medical treatment [24]. We previously reported that %CSA<5 was higher in patients with ACO than in patients with COPD and inhaled corticosteroid (ICS)/long acting beta-agonist (LABA) treatment decreased %CSA<5 over 3 months in the ACO patients [35]. Vascular endothelial growth factor (VEGF) has an important role for the pathogenesis of several lung diseases [36]. In COPD, VEGF and VEGF receptor 2 are decreased, which causes the destruction of alveolar walls (emphysema) and loss of pulmonary microvessels [37]. On the contrary, airway inflammation occurs in response to increased secretion of VEGF in asthma, which leads to abnormal vascularity and increased vessel size [38]. These difference in microvessels might lead to the difference in change of %CSA<5 we observed. Regarding the response to treatment, although previous studies reported that patients with ACO have a worse clinical course than patients with COPD alone [32, 39], recent studies have found that patients with ACO have a better prognosis [8, 9]. Suzuki et al. demonstrated that appropriate treatment improved the clinical course of patients with COPD with asthma-like features due to a better response to treatment [9]. Furthermore, Cosio et al. found that patients with ACO had a better 1-year prognosis than patients with COPD alone [8]. Therefore, various patient factors may affect the changes in %CSA<5 observed in both groups.

There was a significant decrease in WA% within patients with COPD alone, but with COPD with asthma-like features there was no significant change in WA% throughout the study period. Several transitional studies found that more airway wall thickening occurs in asthma than in COPD or controls [40, 41]. Patients with ACO had significantly greater wall thickening than those with COPD alone [25]. In addition, respiratory medications such as ICS and bronchodilators decreased airway wall thickening in both asthma and COPD [42, 43]. We previously demonstrated that the changes of airway wall thickness in patients with COPD alone may be associated to smoking cessation and appropriate treatment [26]. In this longitudinal study, the COPD patients with asthma-like features were more likely to have a severe GOLD stage at enrollment. Several previous reports also found that patients with ACO had lower FEV1% at enrollment [39, 44]. We propose that more severe GOLD stage and greater airway remodeling were associated with the lesser change in WA% in patients with COPD with asthma-like features.

Another reason for no significant change in WA% among patients with COPD with asthma-like features may be that they had fewer features of asthma by our criteria compared to the criteria for ACO [5]. In the present study, 13 patients (48%) with COPD with asthma-like features had only one or two features of asthma. However, in a large cohort study (the COPD History Assessment in Spain (CHAIN) study), the diagnostic criteria required for ACO was one major criterion (bronchodilator test >400 mL and 15% and past medical history of asthma) or two minor criteria (blood eosinophils > 5%, IgE > 100 IU/mL, or two separate bronchodilator tests > 200 mL and 12%) [8]. We consider that the number of asthma-like features possibly may be associated with a decrease in WA% due to response to treatment.

Although there are few randomized clinical studies to provide guidance for the treatment of ACO, treatment with ICS is recommended for patients with ACO, like as for patients with asthma [5]. Recently, GOLD guideline recommends the treatment containing ICS for patients with high eosinophil counts in COPD [45]. In this study, the rate of ICS (including ICS/LABA) use was increased during the follow-up period. About 75 percent of patients with COPD with asthma-like features used ICS and ICS/LABA 2 years later. These findings support the strategy of considering treatment with ICS in patients with COPD with asthma-like features, even if they have not been already diagnosed with ACO [8, 9].

Limitations

Our study has several limitations. First, the study only enrolled a small number of patients and was a preliminary and exploratory investigation conducted at a single institute. Second, the observational period of two years was relatively short. Third, because of the small number of subjects we could not evaluate each CT parameter for differences in treatment, with or without ICS, rate of smoking cessation, and frequency of exacerbations. Further prospective studies with larger study populations and longer observational period are required to confirm these results.

Conclusions

In conclusion, emphysematous regions (LAA%) increased over time in patients with COPD with and without asthma-like features. The %CSA<5 and the WA% at the distal bronchi did not change in parallel with LAA in either group. Furthermore, the change in %CSA<5 over time in COPD with asthma- like features was significantly different than in COPD alone. Patients with COPD with asthma-like features may have different longitudinal structural changes compared to those observed in COPD patients.

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11 Sep 2019

PONE-D-19-20122

Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features

PLOS ONE

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Additional Editor Comments:

This is an interesting topic, especially because morphological features of the chronic progressive disease was followed. But there are some things that need to be improved prior to the decision about publication.

In the Methods section (MDCT) there is a need to clarify in more details how this was done: “All data were analyzed independently by two pulmonologists (RA and YM) who were blinded to all patient clinical information.” How the blinding was provided? Were they blinded also for the sequence (baseline and follow up)? How was the result calculated?

There is no data on sample size calculation and why this size of sample was used for this research. Please provide this! Also provide the Flowchart of the patients according to the STROBE! Please also provide the STROBE checklist!

In the Statistical analysis for the comparison of the follow up data an appropriate method of the analysis should be used – analysis of variance for repeated measurements. Please repeat your analyses using this method and report the results.

In Table 1 please express the rate of exacerbations per 1 year as this is the usual way to do it.

In Table 2 there is variable that is not explained anywhere – V50/V25. Please explain or remove if this is a mistake.

For Figure 1 there is no explanation on which data is represented on the box and whiskers plots! Please add this to your legend. Also it would be more appropriate if you would present the data for each variable for the comparing groups beside each other and not separately for each group. Please correct this. Also it would be better if you would present line graphs instead of box-plots.

In Discussion section there are too many speculations about possible mechanism like: “Indeed, interleukin (IL)-6 known as inflammatory biomarker was associated with emphysema progression (LAA) as assessed by CT scans in COPD [35]. Our data indicates that emphysematous destruction progresses in both patients with COPD and those with COPD with asthma-like features due to persistent airway inflammation even after smoking cessation.” or “We speculate that appropriate treatment, including ICS, decreases bronchial inflammation, which reduces vascular alterations near the small airways.”

Please correct this because these speculations could not be based or associated with you research results.

Please add the difference in management and other patient characteristics (smoking cessation rate) to the Limitations section of the manuscript.

Please change the last sentence in the Conclusions because it represents a too farfetched assumption.

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Reviewers' comments:

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Reviewer #1: Yes

**********

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Reviewer #1: I Don't Know

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Reviewer #1: Yes

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Reviewer #1: I believe this is an important clue in the puzzle of COPD. This study should prompt more bigger studies to clarify the asthma COPD difference. I personally do not support the ACO but believe that patient can have both diseases in different ratios. Regards.

**********

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15 Nov 2019

RESPONSE TO EDITOR:

EVALUATION: This is an interesting topic, especially because morphological features of the chronic progressive disease was followed. But there are some things that need to be improved prior to the decision about publication.

RESPONSE: We greatly appreciate the editor’s constructive comments, which have helped us to considerably improve the quality of our manuscript. We have revised our manuscript according to the editor’s comments. For easy reference, we have provided the revised text in red font.

COMMENT 1: In the Methods section (MDCT) there is a need to clarify in more details how this was done:“All data were analyzed independently by two pulmonologists (RA and YM) who were blinded to all patient clinical information.” How the blinding was provided? Were they blinded also for the sequence (baseline and follow up)? How was the result calculated?

RESPONSE:

We appreciate your helpful comment. The MDCT measurements were evaluated by two pulmonologists (RA and YM) independently. All information including the MDCT data were anonymized and the observers were blinded to other characteristics of the subjects when imaging analysis were performed.

We have revised the manuscript and added the following sentences in the Materials and methods section regarding MDCT measurements (Page 5).

Page 5, lines 133-135, in Materials and methods

Before:

“All data were analyzed independently by two pulmonologists (RA and YM) who were blinded to all patient clinical information.”

After:

“The MDCT measurements were evaluated independently by two pulmonologists (RA and YM). All data were anonymized and the observers were blinded to other characteristics of the subjects when the imaging analyses were performed.”

COMMENT 2: There is no data on sample size calculation and why this size of sample was used for this research. Please provide this! Also provide the Flowchart of the patients according to the STROBE! Please also provide the STROBE checklist!

RESPONSE: We thank the editor for these important comments. We have rechecked the STROBE checklist 1 and have added a flow chart of the study participants as Figure1 below.

We have also calculated the required sample size by JMP 13.0. The number of subjects needed for comparison of the two groups is 118 when the level of significance is 0.05, power (1-β) is 0.8, the difference is 0.1, and standard deviation is 0.2 2. However, the present study is an observational, preliminary, and exploratory study. A few previous studies on longitudinal structural changes have used these three CT parameters (LAA%, WA%, CSA%) mentioned in the present study in patients with COPD 2, 3. Tanabe et al. reported the impact of exacerbations on emphysema progression in COPD 4. They compared the change over two years in CT parameters related to emphysematous progression between the exacerbation group (n=34) vs a non-exacerbation group (n=26). In our previous study, we evaluated the change in three CT parameters in COPD (n=58) for two years 2 and described the morphological changes in the following groups: exacerbation (n=14) and non-exacerbation (n=44), and ex-smokers (n=46) and current smokers (n=12).

There are also a few studies on longitudinal structural changes using CT parameters in patients with ACO or those with COPD with asthma-like features. We have reported previously radiological findings between baseline and following budesonide/formoterol treatment in 20 patients with ACOS 3. Another report described CT parameters for emphysema and airway wall thickening between three groups: COPD group (n=118), ACOS group (n=32), and asthma with airflow limitation (n=27) 5. The present study had a small number of subjects with COPD with asthma-like features similar to these previous studies, and is therefore a preliminary and exploratory study. Accordingly, based on the sample size calculation and the advice of the statistician of our institution we consider it is better that the study is defined as a preliminary investigation. However, we would like to elucidate our findings in a further multi-center cohort study on a large number of subjects according to the editor’s very helpful insights.

We have revised the manuscript in the Limitation section.

Page 13, lines 299-300, in Limitation

Before:

“First, our sample size was small because this study was conducted at a single institute.”

After:

“First, the study only enrolled a small number of patients and was a preliminary and exploratory investigation conducted at a single institute”

We have also revised the manuscript and added the following text in the Materials and methods section regarding subjects (Page 3). We also added a flowchart of the patients as new Figure1 in the manuscript (Page 4).

Page 3, lines 74-81, in Materials and methods

“This prospective observational study enrolled 137 patients who presented to Chiba University Hospital from June 2010 to August 2016 for the management of COPD. Patients were excluded if they had abnormal lung parenchymal lesions other than emphysematous change. At enrollment, 10 patients were excluded for the following reasons: 4 interstitial pneumonia, 1 infectious pneumonia, 1 old pulmonary tuberculosis, and 4 lung cancer or nodules. At the follow up period, 15 patients were excluded: 6 interstitial pneumonia, 2 infectious pneumonia, 3 lung cancer or nodules, 2 cardiac failure, and 2 pleural effusion. Finally, 50 patients with COPD and 29 patients with COPD with asthma-like features were enrolled in the study (Figure 1).”

Fig 1. Flow chart of the study participants

COMMENT 3: In the Statistical analysis for the comparison of the follow up data an appropriate method of the analysis should be used – analysis of variance for repeated measurements. Please repeat your analyses using this method and report the results.

RESPONSE: We thank the editor for this comment. In accordance with the comment, we performed a repeated measure two factorial ANOVA. There was a significant relationship between the change in %CSA<5, and the interaction between COPD/ACO and elapsed time (P=0.003)

The present study consisted of two groups and we measured each parameter two times. In previous reports using MDCT parameters 2, 4, the longitudinal changes within each two groups measured two times were evaluated by the Wilcoxon signed-rank test. For the longitudinal changes between the two groups, the difference between baseline and follow-up in each group was compared using the Mann-Whitney U test.

We consulted regarding this point with the statistician at our institution. Finally, we decided to compare the longitudinal changes within each group in this preliminary study using the Wilcoxon signed-rank test. For longitudinal changes between the two groups, we compared differences in the changes using the Mann-Whitney U test. The results of the annual change in lung function and computed tomography parameters are shown in the new Table 3 as below.

Page 8-9, in Results

Table 3. Annual changes in CAT score, PFTs, and CT measurements: Intra- and inter-group comparisons between patients with COPD with and without asthma-like features

COPD COPD with asthma-like features P value

(between groups)

Value P value

(within group) Value P value

(within group)

CAT score -0.1 ± 3.0 NS 0.3 ± 1.8 NS NS

FEV1 (L) -0.01 ± 0.11 NS -0.02 ± 0.08 NS NS

FEV1% predicted (%) 0.010 ± 0.086 NS -0.001 ± 0.054 NS NS

LAA% (%) 0.83 ± 1.72 < 0.0001 0.40 ± 0.53 < 0.0001 NS

%CSA<5 (%) 0.051 ± 0.104 0.0074 -0.035 ± 0.094 0.0148 0.0007

Mean　WA% (%)

Third -0.007 ± 0.037 NS 0.002 ± 0.027 NS NS

Fifth -0.011 ± 0.025 0.0043 -0.004 ± 0.021 NS NS

We have revised and added the following sentences to the Results section regarding CT parameters (Page 10).

Page 10, lines 210-217, CT parameters in Results

“The annual changes in %CSA<5 were significantly different between the two groups (COPD vs asthma-like features: 0.051 ± 0.104 vs. -0.035 ± 0.094, P=0.0007). On the other hand, the mean WA% at the distal bronchi significantly decreased in the COPD group (baseline vs two years later: 83.9 ± 3.2% vs 82.0 ± 4.6%, P = 0.0043), while the WA% in the COPD with asthma-like features group did not significantly change during the follow-up period (baseline vs two years later: 83.9 ± 3.5% vs 83.2 ± 4.0%, not significant). The annual changes in mean fifth WA% were not significantly different between the two groups (COPD vs asthma-like features: -0.011 ± 0.025 vs -0.004 ± 0.021, not significant).”

We have revised the manuscript and added the following text in the Materials and methods section regarding the statistical analysis (Page 5-6).

Page 5, lines 138-141, the statistical analysis in the Materials and methods

“JMP 13.0 software was used for all statistical analyses (SAS Institute, Cary, NC), with the results expressed as mean (± standard deviation) unless otherwise indicated. Comparison of longitudinal changes in CT parameters, PFTs, and CAT scores between enrollment and follow-up in each group was performed using the Wilcoxon signed-rank test. Comparisons were performed with a chi-square test for categorical variables. Differences in the data between the patients with COPD or COPD with asthma-like features were analyzed using the Mann-Whitney U test.”

COMMENT 4: In Table 1 please express the rate of exacerbations per 1 year as this is the usual way to do it.

RESPONSE: We have revised this in accordance with the editor's comment (Table 1, Page 7).

Page 7, in Table 1

COPD COPD with asthma-like features P value

Exacerbations per 1 year 0.8 ± 0.5 1.6 ± 1.9 NS

COMMENT 5: In Table 2 there is variable that is not explained anywhere – V50/V25. Please explain or remove if this is a mistake.

RESPONSE: We appreciate your helpful comment. We have revised the table in accordance with the comment (Page 8).

Page 8, lines 178-179, in abbreviations of Table 2

“V50/V25, forced expiratory flow at 50% vital capacity and forced expiratory flow at 25% vital capacity”

COMMENT 6: For Figure 1 there is no explanation on which data is represented on the box and whiskers plots! Please add this to your legend. Also it would be more appropriate if you would present the data for each variable for the comparing groups beside each other and not separately for each group. Please correct this. Also it would be better if you would present line graphs instead of box-plots.

RESPONSE: We appreciate the reviewer’s helpful comment. We have revised the figure as a new Figure 2 in accordance with the comment). We have shown comparisons of the data for each variable in the groups beside each other, instead of separately using line graphs. We have also added an explanation of the CT parameters in the Figure legend in the Results section.

Fig 2. Changes in radiological parameters over two years of follow-up

Before:

After:

Page 9, line 219-223, in Results section

Notes: Radiological parameters were compared between enrollment and two-year follow-up using the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi.

Abbreviations: ALF, asthma-like features; LAA, low-attenuation area; CSA<5, the cross-sectional area of pulmonary vessels < 5 mm2; WA%, wall area percentage; NS, not significant

COMMENT 7: In Discussion section there are too many speculations about possible mechanism like: “Indeed, interleukin (IL)-6 known as inflammatory biomarker was associated with emphysema progression (LAA) as assessed by CT scans in COPD [35]. Our data indicates that emphysematous destruction progresses in both patients with COPD and those with COPD with asthma-like features due to persistent airway inflammation even after smoking cessation.” or “We speculate that appropriate treatment, including ICS, decreases bronchial inflammation, which reduces vascular alterations near the small airways.”

Please correct this because these speculations could not be based or associated with you research results.

Please add the difference in management and other patient characteristics (smoking cessation rate) to the Limitations section of the manuscript.

Please change the last sentence in the Conclusions because it represents a too farfetched assumption.

RESPONSE:

We appreciate this important comment. We have revised and added the following text in the Abstract, Discussion, and Conclusion section.

Page 1, lines 21-22, Conclusion in Abstract

Before:

“Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Appropriate medical management may have a different effect on structural changes in COPD with and without asthma-like features.”

After:

“Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Patients with COPD with asthma-like features may have different longitudinal structural changes than those seen in COPD patients.”

We revised the Discussion.

Page 11, lines 241-246, in Discussion

Before:

“Exposure to tobacco smoke leads to chronic airway inflammation through the activation of inflammatory cells [33]. Regardless of smoking cessation, chronic inflammation persists [34] and causes emphysema progression [21]. In our study, most patients were past smokers, and all had a significant smoking history. Indeed, interleukin (IL)-6 known as inflammatory biomarker was associated with emphysema progression (LAA) as assessed by CT scans in COPD [35]. Our data indicates that emphysematous destruction progresses in both patients with COPD and those with COPD with asthma-like features due to persistent airway inflammation even after smoking cessation.”

After:

“In COPD, exposure to tobacco smoke leads to chronic airway inflammation through the activation of inflammatory cells [33]. Regardless of smoking cessation, chronic inflammation persists [34] and causes emphysema progression [21]. Therefore, our data indicates that emphysematous destruction may progress in both patients with COPD and those with COPD with asthma-like features due to the fact that airway inflammation persist even after smoking cessation.”

Page 11-12, lines 261-268, in Discussion

Before:

“Moreover, appropriate treatment might reduce the %CSA<5 in the COPD patients with asthma-like features. Although previous studies reported that patients with ACO have a worse clinical course than patients with COPD alone [32, 40], recent studies have found that patients with ACO have a better prognosis [8, 9]. Suzuki et al. demonstrated that appropriate treatment improved the clinical course of patients with COPD with asthma-like features due to a better response to treatment [9]. Furthermore, Cosio et al. found that patients with ACO had a better 1-year prognosis than patients with COPD alone [8].”

After:

“Regarding the response to treatment, although previous studies reported that patients with ACO have a worse clinical course than patients with COPD alone [32, 39], recent studies have found that patients with ACO have a better prognosis [8, 9]. Suzuki et al. demonstrated that appropriate treatment improved the clinical course of patients with COPD with asthma-like features due to a better response to treatment [9]. Furthermore, Cosio et al. found that patients with ACO had a better 1-year prognosis than patients with COPD alone [8]. Therefore, these various patient factors may affect the changes in %CSA<5 observed in both groups.”

Page 12-13, lines 294-296, in Discussion

Before:

“Optimal management including ICS reduces the airway inflammation and may provide a greater effect on patients with COPD with asthma-like features.”

After:

“These findings support the strategy of considering treatment with ICS in patients with COPD with asthma-like features, even if they have not been already diagnosed with ACO [8, 9].”

We have also revised and added differences in management and other patient characteristics (smoking cessation rate) to the Limitations section of the manuscript.

Page 13, lines 301-304, in Limitation

“Third, because of the small number of subjects we could not evaluate each CT parameter for differences in treatment, with or without ICS, rate of smoking cessation, and frequency of exacerbations. Further prospective studies with larger study populations and longer observational period are required to confirm these results.”

The Conclusion has been revised as follows.

Page 13, lines 310-312, in Conclusion

Before:

“Management strategies may have different effects on pulmonary vascularity between COPD with and without asthma-like features.”

After:

“Patients with COPD with asthma-like features may have different longitudinal structural changes compared to those observed in COPD patients.

RESPONSE TO REVIEWER:

EVALUATION: I believe this is an important clue in the puzzle of COPD. This study should prompt more bigger studies to clarify the asthma COPD difference. I personally do not support the ACO but believe that patient can have both diseases in different ratios. Regards.

RESPONSE:

We greatly appreciate your helpful and important insights on the subjects with asthma-COPD overlap (ACO). As the reviewer has commented, the pathogenesis and physiological findings are distinct between COPD and asthma 6. Recently, ACO has been recognized in clinical practice. Although GINA/GOLD published a consensus on ACO 7, the diagnosis of ACO has not been defined definitively, and previous studies have used multiple different diagnostic criteria 8. On the other hand, some patients with COPD have asthma-like features 9, even if they have not been diagnosed with ACO. Several previous reports have described the characteristics of ACO and COPD with asthma-like features 3, 9, 10. COPD with asthma-like features might be a clinical phenotype of COPD, and identifying this phenotype is used for designing individualized treatments 9, 11, 12. We consider that larger studies on COPD, asthma, and ACO are required in the near future in order to elucidate the characteristics of each phenotype 13, 14.

References

1. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014; 12: 1495-9.

2. Takayanagi S, Kawata N, Tada Y, et al. Longitudinal changes in structural abnormalities using MDCT in COPD: do the CT measurements of airway wall thickness and small pulmonary vessels change in parallel with emphysematous progression? Int J Chron Obstruct Pulmon Dis. 2017; 12: 551-60.

3. Suzuki T, Tada Y, Kawata N, et al. Clinical, physiological, and radiological features of asthma-chronic obstructive pulmonary disease overlap syndrome. Int J Chron Obstruct Pulmon Dis. 2015; 10: 947-54.

4. Tanabe N, Muro S, Hirai T, et al. Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011; 183: 1653-9.

5. Kitaguchi Y, Yasuo M and Hanaoka M. Comparison of pulmonary function in patients with COPD, asthma-COPD overlap syndrome, and asthma with airflow limitation. Int J Chron Obstruct Pulmon Dis. 2016; 11: 991-7.

6. Barnes PJ. Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases. Am J Respir Crit Care Med. 2006; 174: 240-3; discussion 3-4.

7. Asthma COPD and Ashtma-COPD Overlap Syndrome (ACOS). Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease 2015. Available from: https://goldcopd.org/asthma-copd-asthma-copd-overlap-syndrome/.

8. Tho NV, Park HY and Nakano Y. Asthma-COPD overlap syndrome (ACOS): A diagnostic challenge. Respirology. 2016; 21: 410-8.

9. Suzuki M, Makita H, Konno S, et al. Asthma-like Features and Clinical Course of Chronic Obstructive Pulmonary Disease. An Analysis from the Hokkaido COPD Cohort Study. Am J Respir Crit Care Med. 2016; 194: 1358-65.

10. Hardin M, Cho M, McDonald ML, et al. The clinical and genetic features of COPD-asthma overlap syndrome. Eur Respir J. 2014; 44: 341-50.

11. Leigh R, Pizzichini MM, Morris MM, Maltais F, Hargreave FE and Pizzichini E. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J. 2006; 27: 964-71.

12. Fattahi F, ten Hacken NH, Lofdahl CG, et al. Atopy is a risk factor for respiratory symptoms in COPD patients: results from the EUROSCOP study. Respir Res. 2013; 14: 10.

13. Hizawa N. LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes. Int J Chron Obstruct Pulmon Dis. 2015; 10: 1093-102.

14. Agusti A, Gea J and Faner R. Biomarkers, the control panel and personalized COPD medicine. Respirology. 2016; 21: 24-33.

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25 Nov 2019

PONE-D-19-20122R1

Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features

PLOS ONE

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Additional Editor Comments (if provided):

Dear Authors,

your manuscript is acceptable for publication after small revisions that should be done on Figures. On Figure 1 please change the words "abnormal chest shadows" into something more appropriate, like "abnormal lung parenchymal lesions other than emphysematous change". On Figure 2, and also the markings for the median and interquartile range for each time point and group.

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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11 Dec 2019

RESPONSE TO EDITOR:

EVALUATION:

Your manuscript is acceptable for publication after small revisions that should be done on Figures. On Figure 1 please change the words "abnormal chest shadows" into something more appropriate, like "abnormal lung parenchymal lesions other than emphysematous change". On Figure 2, and also the markings for the median and interquartile range for each time point and group.

RESPONSE:

We greatly appreciate the editor’s constructive comments which have helped us to considerably improve the quality of our manuscript. We have revised our manuscript according to the editor’s comments.

1) We revised Figure 1 according to the editor’s comment.

Fig 1. Flow chart of the study participants

2) We also revised Figure 2 according to the editor’s comment. We have added bars at which represent the median and interquartile range (Page 11).

Fig 2. Changes in radiological parameters over two years of follow-up

Page 11, lines 220-223, in Results

Before:

“Notes: Radiological parameters were compared between enrollment and two-year follow-up with the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi.”

After:

“Notes: Radiological parameters were compared between enrollment and two-year follow-up with the Wilcoxon signed-rank test. WA% shows the mean wall area percentage at the 5th generation of bronchi. The thick horizontal bars at the sides of each graph show the median, while the thin horizontal bars at the sides of each graph show the interquartile range.”

Submitted filename: Response submission(1205).docx

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13 Dec 2019

Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features

PONE-D-19-20122R2

Dear Dr. Naoko Kawata,

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PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

after you have made the requested changes your manuscript is acceptable in this form for publication in PLOS ONE.

Reviewers' comments:

18 Dec 2019

PONE-D-19-20122R2

Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features

Dear Dr. Kawata:

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on behalf of

Dr. Davor Plavec

Academic Editor

PLOS ONE