Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: Relationship with pulmonary function and clinical events.

BACKGROUND: Combined pulmonary fibrosis with emphysema (CPFE) is a clinically meaningful syndrome characterized by coexisting upper-lobe emphysema and lower-lobe interstitial fibrosis. However, ambiguous diagnostic criteria and, particularly, the absence of objective methods to quantify emphysematous/fibrotic lesions in patients with CPFE confound the interpretation of the pathophysiology of this syndrome. We analyzed the relationship between objectively quantified computed tomography (CT) measurements and the results of pulmonary function testing (PFT) and clinical events in CPFE patients.
MATERIALS AND METHODS: We enrolled 46 CPFE patients who underwent CT and PFT. The extent of emphysematous lesions was obtained by calculating the percent of low attenuation area (%LAA). The extent of fibrotic lesions was calculated as the percent of high attenuation area (%HAA). %LAA and %HAA values were combined to yield the percent of abnormal area (%AA). We assessed the relationships between CT parameters and other clinical indices, including PFT results. Multivariate analysis was performed to examine the association between the CT parameters and clinical events.
RESULTS: A greater negative correlation with percent predicted diffusing capacity of the lung for carbon monoxide (DLCO %predicted) existed for %AA (r = -0.73, p < 0.001) than for %LAA or %HAA alone. The %HAA value was inversely correlated with percent predicted forced vital capacity (r = -0.48, p < 0.001), percent predicted total lung capacity (r = -0.48, p < 0.01), and DLCO %predicted (r = -0.47, p < 0.01). Multivariate logistic regression analysis found that %AA showed the strongest association with hospitalization events (odds ratio = 1.20, 95% confidence interval = 1.01-1.54, p = 0.029).
CONCLUSION: Quantitative CT measurements reflected deterioration in pulmonary function and were associated with hospitalization in patients with CPFE. This approach could serve as a useful method to determine the extent of lung morphology, pathophysiology, and the clinical course of patients with CPFE.

Background

Combined pulmonary fibrosis with emphysema (CPFE) is characterized by the coexistence of upper-lobe emphysema and lower-lobe fibrosis. Cottin et al. proposed the term “CPFE” for the entity characterized by these radiological features, a preserved lung volume, and severely diminished capacity for gas exchange [1]. The coexistence of emphysema and pulmonary fibrosis in individual patients is not rare in clinical practice. The estimated prevalence of pulmonary fibrosis is 8% in patients with stage 2 or higher chronic obstructive pulmonary disease (COPD) [2], and approximately 30% of patients with idiopathic pulmonary fibrosis (IPF) show manifestations of emphysema on chest computed tomography (CT) [3]. CPFE usually develops in men who are commonly older than 60 years of age and are current or ex-smokers, which is similar to the epidemiology of IPF [4, 5]. Follow-up studies have found that the prognosis of patients with CPFE is very poor, because of complications such as severe pulmonary hypertension, lung cancer, and acute exacerbations (AEs) [3, 6–8].

Patients with CPFE show severely reduced diffusing capacity of the lung for carbon monoxide (DLCO), mild airflow limitation, and preserved lung capacity [9]. The baseline value for percent predicted DLCO (DLCO %predicted) is lower in patients with CPFE than in patients with COPD without pulmonary fibrosis [10] or in patients with IPF alone [11]. The respective annual decreases in vital capacity (VC) and DLCO were significantly smaller and larger in patients with CPFE than in patients with IPF [11]. The findings on pulmonary function testing (PFT) of CPFE patients are the results of additive effects or the counterbalance between the restrictive effects of pulmonary fibrosis and the hyperinflation associated with emphysematous lesions [9].

On the other hand, for patients with CPFE, several studies have reported on the correlations between radiological morphological findings and pulmonary function [12, 13]. Subjective visual assessments of emphysematous/fibrotic lesions on radiological imaging have been commonly performed. However, objective quantitative assessments are needed to clarify the relationships between morphological findings and the physiological characteristics of the disease, and to allow reproducible and longitudinal multicenter studies. A few recent studies used multidetector computed tomography (MDCT) to perform simultaneous objective quantitative assessments of the extent of emphysema and fibrosis in patients with CPFE and determined the association between the morphological findings and pulmonary dysfunction [14, 15]. However, whether these objective assessments are associated with the clinical manifestations of patients with CPFE has not been established.

Thus, the aims of this study were as follows: first, to evaluate the correlations between PFT results, including DLCO, and the extent of emphysematous/fibrotic lesions as reflected by quantitative CT measurements; and second, to assess these CT measurements in relation to the factors associated with clinical events in patients with CPFE.

Materials and methods

Participants

The study protocol conformed to the Declaration of Helsinki and was approved by the Ethics Committee of our university (approval numbers: 857 and 2083), and written informed consent was obtained from all study participants.

We enrolled 113 patients who presented to our hospital between July 2012 and August 2018 for CPFE management. CPFE was diagnosed according to CT criteria described by Cottin et al., as follows: 1) the presence of a predominantly upper lobe emphysema, defined as well-demarcated areas of decreased attenuation, marginated by a very thin (< 1 mm) or no wall, and/or multiple bullae (> 1 cm); and 2) the presence of predominantly peripheral and basal pulmonary fibrosis, defined as reticular opacities and traction bronchiectasis with or without honeycombing [1]. Emphysema was classified into the following 3 groups: centrilobular, paraseptal, and mixed type (centrilobular plus paraseptal) emphysema. The patterns of pulmonary fibrosis were classified according to the IPF guidelines into usual interstitial pneumonia (UIP), probable UIP, indeterminate for UIP, and alternative-diagnosis pattern [5]. The classification of the patterns of pulmonary emphysema and fibrosis were performed independently by 3 clinical pulmonologists (MS, NK, and JI) who were blinded to the clinical information of the study patients.

We finally enrolled 46 patients with CPFE (Fig 1) after eliminating those with the following exclusion criteria: 1) lung cancer (n = 24); 2) connective tissue disease (n = 18); 3) systemic glucocorticoid treatment (n = 4); 4) infectious disease, including mycobacterial disease and aspergillosis (n = 3); 5) thoracic surgery (n = 2); 6) chemotherapy (n = 2); 7) heart failure (n = 0); and 8) others (n = 14).

Fig 1

Study population.

A total of 46 patients with combined pulmonary fibrosis with emphysema were included. Abbreviations: CPFE, combined pulmonary fibrosis with emphysema; RA, rheumatoid arthritis; SjS, Sjögren syndrome; MPA, microscopic polyangiitis.

MDCT examinations

All patients underwent 64-MDCT (Aquilion ONE and Aquilion PRIME; Canon Medical Systems, Tokyo, Japan) and were scanned from the thoracic inlet to the diaphragm during full inspiration without contrast enhancement. The MDCT scan parameters were as follows: collimination, 0.5 mm; 120 kV; auto-exposure control; gantry rotation time, 0.5 second; and beam pitch, 0.83. All images were reconstructed by standard algorithms (FC07) 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.

Quantitative CT measurements

We selected 4 CT slices from each CT series as follows: the first upper lung slice was taken 1 cm above the upper margin of the aortic arch (upper lesion), the second upper lung slice was taken at the carina (middle lesion), the first lower lung slice was taken 1 cm below the right inferior pulmonary vein (lower lesion), and the second lower lung slice was taken at the lower edge of the heart (bottom lesion). High-resolution computed tomography (HRCT) images were analyzed by an image-processing program (ImageJ, version 1.51j8, available at http://rsb.info.nih.gov/ij/; National Institutes of Health, Bethesda, MD, USA).

The quantitative measurements were performed in accordance with Matsuoka et al. [14, 16]. We used a threshold technique to segment all the pixels between -200 and -1024 Hounsfield units (HU) as the total lung area (TLA). To determine the extent of emphysema, we segmented pixels lower than -950 HU as the low attenuation area (LAA; Fig 2A and 2B), and %LAA was calculated for each slice as the percent of LAA relative to TLA. Similarly, to determine the extent of interstitial fibrotic lesions, we segmented all the pixels greater than -700 HU as the high attenuation area (HAA; Fig 2C and 2D); and %HAA was calculated for each slice as the percent of HAA relative to TLA. To calculate the total area of emphysematous and fibrotic changes, the percent of abnormal area (%AA) was obtained by summing the values for %LAA and %HAA at each thoracic level. The %LAA, %HAA, and %AA were calculated as the mean values of %LAA, %HAA, and %AA in each CT slice, respectively. These data were confirmed independently by 2 pulmonologists (MS and NK). All data were anonymized, and the observers were blinded to other characteristics of the participants when the imaging analysis was performed.

Fig 2

Axial computed tomography (CT) images of the upper (a) and lower lungs (c). Pixels with attenuation values between -950 and -1024 Hounsfield units (HUs) (b) and greater than -700 HUs (d) are highlighted in black on the CT scans.

Pulmonary function testing

All study participants underwent PFT by a CHSTAC-8900 spirometer (Chest MI, Tokyo, Japan). PFT was performed in accordance with the guidelines of the American Thoracic Society and European Respiratory Society [17]. Total lung volume was determined by the helium dilution method, and DLCO and alveolar ventilation were determined by the single-breath method. The values for percent predicted forced expiratory volume in 1 second (FEV1%predicted) were calculated according to the equations of the Japanese Respiratory Society [18].

Clinical events

We investigated clinical events (hospitalizations, AEs, and deaths) during the observation period. The diagnosis of AEs was based on the AE criteria for IPF, as follows [19]: 1) acute worsening or development of dyspnea, typically < 1 month duration, 2) new bilateral ground-glass opacity and/or consolidation on CT, and 3) deterioration not fully explained by cardiac failure or fluid overload. In addition, duration of follow-up, smoking history, and serum levels of Krebs von den Lungen-6 (KL-6) were determined.

Statistical analysis

Results are expressed as means ± standard deviation (± SD) or as medians (interquartile range [IQR]) as appropriate. Intraclass correlation coefficients (ICC) were determined to assess the intra- and interobserver reliability of CT measurements. After confirmation of the normality of the data on study parameters, the correlations between CT measurements and the results of PFT were assessed by Spearman rank correlation analysis, as appropriate. Comparisons between the group of patients with and without hospitalization events were performed by the Mann-Whitney U test. Multivariate regression analysis was performed to identify which variables were associated with hospitalization events. The variables that were significant in the univariate model were then entered into a multivariate regression analysis to identify the independent determinants of hospitalization events. For all analyses, the null hypothesis was rejected at the 5% level. Statistical analysis was performed by JMP 13.0 software (SAS Institute, Cary, NC).

Results

Patient characteristics

The general characteristics of the 46 enrolled CPFE patients are shown in Table 1. The mean age was 67.2 ± 7.8 years, and the 97.8% of patients were males. The mean body mass index (BMI) was 24.0 ± 3.7 kg/m2. Except for 1 participant, all patients had a smoking history, and a mean of 62.0 ± 41.2 pack-years. The mean duration of follow-up was 1,087.9 ± 574.5 days.

Table 1

Patient characteristics, pulmonary function tests, and computed tomography measurements.

	Mean ± SD
Age (years)	67.2 ± 7.8
Male/female, n (%)	45 (97.8%)/1 (2.2%)
BMI (kg/m2)	24.0 ± 3.7
Pack years	62.0 ± 41.2
Smoker (Current or ever/never)	45 (97.8%)/1 (2.2%)
Follow-up duration (days)	1087.9 ± 574.5
KL-6 (U/mL)	1038.8 ± 1041.0
Pulmonary function tests
FVC (L)	3.1 ± 0.8
FVC %predicted (%)	86.7 ± 20.3
FEV1%predicted (%)	81.8 ± 18.3
FEV1/FVC (%)	77.9 ± 9.3
FRC %predicted (%)	81.8 ± 16.6
RV %predicted (%)	83.3 ± 21.2
TLC (L)	4.7 ± 1.0
TLC %predicted (%)	84.3 ± 15.9
DLCO (mL/min/mmHg)	11.7 ± 4.6
DLCO %predicted (%)	65.4 ± 23.3
CT measurements
Emphysema type (centrilobular/paraseptal/mixed type)	21/17/8
Fibrosis type (UIP/probable UIP/indeterminate for UIP/alternative diagnosis pattern)	15/19/10/2
%LAA (median [IQR]) (%)	4.9 (1.9–8.5)
%HAA (median [IQR]) (%)	20.2 (15.4–25.6)
%AA (median [IQR]) (%)	25.5 (21.0–36.2)
Clinical events
Hospitalization, n (%)	8 (17.4%)
Acute exacerbation, n (%)	2 (4.3%)
Death, n (%)	3 (6.5%)

Abbreviations: BMI, body mass index; KL-6, Krebs von den Lungen-6; UIP, usual interstitial pneumonia; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity; DLCO, diffusing capacity of the lung for carbon monoxide; %LAA, percent of low attenuation area to total lung area; %HAA, percent of high attenuation area to total lung area; %AA, percent of abnormal area to total lung area.

PFT and CT measurements

The results of PFT and quantitative CT measurements are presented in Table 1. The mean percent predicted forced vital capacity (FVC %predicted), the mean FEV1%predicted, the mean percent predicted total lung capacity (TLC %predicted), and the mean DLCO %predicted were 86.7 ± 20.3%, 81.8 ± 18.3%, 84.3 ± 15.9%, and 65.4 ± 23.3%, respectively.

Study participants were classified by emphysema type as centrilobular (n = 21), paraseptal (n = 17), and mixed (n = 8) type. Regarding the pattern of pulmonary fibrosis, the patients were categorized as UIP (n = 15), probable UIP (n = 19), indeterminate for UIP pattern (n = 10), and alternative diagnosis (n = 2).

The median (IQR) %LAA, %HAA, and %AA were 4.9% (1.9–8.5%), 20.2% (15.4–25.6%), and 25.5% (21.0–36.2%), respectively. The CT measurements showed excellent reproducibility. The ICC for intraobserver variability among the CT parameters were as follows: %LAA, 0.998 (95% confidence interval [CI], 0.997–0.999); %HAA, 0.998 (0.996–0.999); %AA, 0.998 (0.996–0.999). The ICC between 2 observers (interobserver variability) for the CT parameters were as follows: %LAA, 0.971 (95% CI, 0.948–0.984); %HAA, 0.994 (0.989–0.997); %AA, 0.984 (0.971–0.991).

The correlations between the CT measurements and the results of PFT are shown in Table 2. The %AA parameter was more negatively correlated with DLCO %predicted (r = -0.73, p < 0.001) than %LAA (r = -0.51, p < 0.001) or %HAA (r = -0.47, p < 0.01) alone. The %AA parameter was also significantly correlated with FVC %predicted, FEV1%predicted, and TLC %predicted. The %HAA parameter was inversely correlated with FVC %predicted, FEV1/FVC, TLC %predicted, and DLCO %predicted. In contrast, no significant correlations between %LAA and the results of PFT existed, except DLCO %predicted. Fig 3 demonstrates the correlations between DLCO %predicted and CT measurements on a two-dimensional analysis plot.

Table 2

Correlations between computed tomography measurements and results of pulmonary function tests.

	%LAA		%HAA		%AA
	r	p value	r	p value	r	p value
FVC %predicted	-0.06	0.69	-0.48	< 0.001	-0.46	< 0.01
FEV1%predicted	-0.29	0.05	-0.29	0.05	-0.45	< 0.01
FEV1/FVC	-0.23	0.12	0.29	< 0.05	0.13	0.41
FRC %predicted	0.11	0.49	-0.41	< 0.01	-0.30	0.06
RV %predicted	0.2	0.22	-0.5	< 0.01	-0.27	0.10
TLC %predicted	-0.02	0.89	-0.48	< 0.01	-0.46	< 0.01
DLCO %predicted	-0.51	< 0.001	-0.47	< 0.01	-0.73	< 0.001

Abbreviations: %LAA, percent of low attenuation area to total lung area; %HAA, percent of high attenuation area to total lung area; %AA, percent of abnormal area to total lung area; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity; DLCO, diffusing capacity of the lung for carbon monoxide.

Fig 3

Correlations of percent predicted diffusing capacity of the lung for carbon monoxide with the percent of low attenuation area, the percent of high attenuation area, and the percent of abnormal area.

Abbreviations: DLCO, diffusing capacity of the lung for carbon monoxide; %LAA, percent of low attenuation area; %HAA, percent of high attenuation area; %AA, percent of abnormal area.

Table 1 also shows a summary of the clinical events. Three patients died of AE of IPF, chronic respiratory dysfunction, or heart failure. Two patients developed an AE. They received systemic corticosteroids and noninvasive oxygenation therapy; 1 patient died and the other recovered. Eight patients were hospitalized for the following reasons: bacterial pneumonia (n = 2), heart failure due to an old myocardial infarction (n = 2), AEs of IPF (n = 2), pneumothorax (n = 1), and other (n = 1). The difference between the duration of follow-up for the participants with or without hospitalization was not significant (median duration 1187 days [627–2373 days] vs 1082 days [21–2255 days]; p = 0.27) (S1 Appendix).

Clinical events and CT measurements

The hospitalization events were related to the parameter, %AA (Fig 4). The results of univariate and multivariate analysis for clinical events are shown in Table 3. The univariate analysis showed that pack-years (odds ratio [OR] = 0.97, 95% CI = 0.93–0.99, p = 0.035), DLCO %predicted (OR = 0.91, 95% CI = 0.82–0.96, p = 0.0006), and %AA (OR = 1.16, 95% CI = 1.06–1.32, p = 0.0005) were significantly associated with hospitalization. Multivariate analysis identified %AA as the only independent factor associated with hospitalization (OR = 1.20, 95% CI = 1.01–1.54, p = 0.029).

Fig 4

Comparison of the percents of abnormal lung areas in participants with vs those without hospitalization.

Abbreviation: %AA, percent of abnormal area.

Table 3

Univariate and multivariate analysis for hospitalization events.

	Univariate		Multivariate
	Odds ratio (95% CI)	p value	Odds ratio (95% CI)	p value
Age	1.00 (0.91–1.11)	0.95
BMI	0.91 (0.74–1.11)	0.33
Pack years	0.97 (0.93–0.99)	0.035	0.97 (0.90–1.01)	0.1733
FVC %predicted	1.07 (0.41–2.99)	0.89
DLCO %predicted	0.91 (0.82–0.96)	0.0006	0.96 (0.86–1.04)	0.3629
%AA	1.16 (1.06–1.32)	0.0005	1.20 (1.01–1.54)	0.0290

Abbreviations: CI, confidence interval; BMI, body mass index; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; %AA, percent of abnormal area to total lung area.

Discussion

The key points of this study are as follows: first, the objective quantified CT values for emphysematous LAA and fibrotic HAA were significantly correlated with evidence of impaired pulmonary function; second, the radiological parameters obtained by MDCT were associated with the clinical course of patients with CPFE.

Although previous studies have demonstrated an association between radiological assessments and pulmonary function in patients with CPFE [12, 13, 20], the objective quantitative methods used for determining the simultaneous extents of emphysema and pulmonary fibrosis have not been fully explored. However, recent studies on quantitative assessment defined the LAA associated with emphysematous lesions as the regions of lung density that are lower than the threshold of -950 HU, and the HAA associated with fibrotic lesions as the regions of lung density that are higher than the threshold of -700 HU [14-16]. Here, we used those CT criteria and confirmed that the CT parameters were significantly correlated with the results of PFT. These data suggest that this quantitative method may be reproducible and might enable us to perform an objective evaluation of abnormal CT findings.

Among the relationships between CT parameters and PFT results, the abnormal area (%AA), which was defined as the sum of %LAA and %HAA, had a greater correlation with a decrease in DLCO %predicted than %LAA or %HAA alone. The DLCO value is one of the most clinically valuable measurements based on the ability of the lungs to transfer gas from inhaled air to the red blood cells [21]. Although most PFT parameters of patients with CPFE have presented various patterns in accordance with specific morphological changes, a severely reduced DLCO value has been seen to be the most common abnormal finding [8, 9]. A decrease in the DLCO value of patients with CPFE is believed to be associated with alveolar destruction, loss of the pulmonary vascular bed, and alveolar wall thickening/collapse due to both emphysema and fibrotic changes [4]. Thus, the additive effect of emphysematous lesions and pulmonary fibrosis in the lungs of CPFE patients might account for the fact that %AA was more strongly associated with a decreased DLCO %predicted value than %LAA or %HAA alone. Additionally, in patients with IPF, decreased DLCO has been correlated with decreased exercise tolerance, including distance obtained during the 6-minute-walk test [22]. Our results indicate that chest CT assessments might reflect pulmonary physiological dysfunction in patients with CPFE as well as in those with IPF.

In addition, %LAA was only correlated with DLCO %predicted, and tended to be associated with the severity of the obstructive impairment. Although a number of studies of patients with COPD have reported on the relationship between LAA and obstructive impairment [23], only a few reports have described the relationship between LAA and pulmonary dysfunctions in CPFE patients [12, 14]. They reported a correlation between %LAA and decreased FEV1%predicted and between %LAA in the upper lung slice and a decline in DLCO %predicted [12, 14]. In patients with CPFE, the increased traction caused by pulmonary fibrosis prevents collapse of the expiratory airway and expiratory airflow limitation, which are associated with emphysema. Therefore, these patients show a preserved FEV1, FRC %predicted, and RV %predicted [4, 9]. Meanwhile, our study showed that %HAA was more strongly correlated with FRC %predicted and RV %predicted than %LAA. Thus, we consider that the extent of emphysema affects the pulmonary function of patients with CPFE less than their fibrotic lesions affect pulmonary function.

Emphysema subtypes are divided into three types; centrilobular, paraseptal, and panlobular [24]. Centrilobular emphysema is commonly complicated by COPD [25], and emphysema subtypes in COPD are related to pulmonary symptoms, the development of lung cancer, and worsening radiological findings [26, 27]. In contrast, CPFE patients are likely to exhibit paraseptal emphysema (30%-65%) [28, 29], which is consistent with the present study. CPFE with paraseptal emphysema lesions is associated with CTD and a poor prognosis [30-32]. Considering emphysema subtypes in CPFE might contribute to the putative clinical course.

Another notable result of this study concerns our investigation of the relationship between objective quantitative CT measurements and the clinical events of patients with CPFE. Only the parameter %AA was significantly independently associated with hospitalization events on multivariate regression analysis of such clinical factors as age, BMI, pack-years, FVC %predicted, DLCO %predicted, and %AA. Respiratory-related hospitalizations have prognostic significance for patients with COPD and IPF [33-35] and are independently associated with decreased FVC in patients with IPF [34]. A previous report has described the relationship between the radiological assessments and clinical events in CPFE [13]. This study used a subjective assessment of CT images that was based on a fibrosis-weighted CT index, and demonstrated a correlation with the outcome in CPFE patients. In our study, we used a simple automated analysis of CT images, and found a significant relationship between %AA and hospitalization. Our results suggest that this radiological assessment might reflect disease severity and have prognostic value for patients with CPFE.

Interestingly, in our study population, the %AA parameter was more relevant to hospitalization than the DLCO %predicted value. Although reduced DLCO is commonly observed in patients with CPFE, the impact of DLCO on outcome has not been clarified. In patients with IPF, not only gender, age, physiological stage, and composite physical index, but also a decrease from baseline DLCO %predicted, are known to be significant predictors of mortality [36]. A decrease in DLCO is also a predictor of exercise intolerance in patients with COPD [37, 38]. Previous studies have reported on the association between radiological assessments and clinical manifestations in IPF and COPD. In IPF patients with stable or exacerbated disease, the extent of fibrotic changes such as reticulation, honeycombing, and traction bronchiectasis has been reported to be a significant predictor for the risk of exacerbation and mortality [39, 40]. Similarly, the extent of emphysematous lung predicts the risk of exacerbation and mortality in patients with COPD [41, 42]. For our CPFE patients, we evaluated the %AA parameter that reflects both emphysematous and fibrotic lesions and found that %AA was an independent predictor for hospitalization.

The reasons for the hospitalization of our study patients varied; almost all hospitalizations were for respiratory- and circulatory-associated conditions such as pneumonia, pneumothorax, AE, and heart failure. These complications were similar to those reported for COPD and IPF patients [43, 44]. Severe pulmonary dysfunction leads to respiratory complications such as pneumonia, pneumothorax, and AEs in both COPD and IPF patients [19, 45, 46]. In patients with COPD, endothelial dysfunction and remodeling of the pulmonary vascular bed are considered to be associated with hypoxia and systemic inflammation, which might contribute to the development of cardiovascular disease [43, 47]. Patients with IPF have an increased risk of vascular disease in comparison with the general population [48]. In CPFE, the unravelling mechanisms in common with COPD and IPF could lead to these complications.

We also found a mild association between smoking pack-years and hospitalization events. Smoke-induced oxidative damage induces regenerating precursor cells in both IPF and COPD, which might lead to abnormal tissue remodeling and functional impairment in these diseases [49]. A positive smoking history has been found to increase mortality in patients with IPF [50]. In patients with COPD, the cessation of smoking reduces the risk of exacerbation [51] and subsequent mortality, even in patients with severe disease [52]. Furthermore, continuous smoking affects the progression of disease in patients with CPFE more strongly than former smoking does [53]. Therefore, the cessation of smoking is considered to essential for patients with CPFE.

Physiological measurements of lung function have been conventionally performed to evaluate disease severity in patients with lung disease. However, computer-based HRCT image analysis has greatly improved, and has enabled us to assess the extent of lung disease and to quantify morphological changes [54, 55]. The recently introduced densitometric- and histogram-based analysis of CT images provides data on mean lung attenuation, skewness, and kurtosis. These parameters have been reported to show associations with parameters of pulmonary function and disease progression in various lung diseases [56]. In addition, some objective CT measurements have been found to be useful for the long-term monitoring of patients with emphysematous and fibrotic lung disease [25, 57, 58]. Quantitative CT assessments, as well as other biomarkers, might be useful for the assessment of disease severity and prediction of the clinical course of patients with CPFE [59].

This study has limitations. First, this was a single-center study with a small number of enrolled patients and the pulmonary function of the subjects was preserved compared to previous studies [1, 4, 6, 12]. The numbers of AEs and hospitalizations were low compared with those numbers in previous studies of patients with COPD, IPF, or CPFE [7, 19, 42]. Second, samples were not taken from patients for a histopathological evaluation. Third, the inner spaces of honeycombing and airspace enlargement associated with fibrosis might have been assessed as LAA. However, reports on the measurement of honeycombing with a background of fibrotic lesions are rare, and methodologies for distinguishing between honeycombing and LAA have not been elucidated [56]. Additionally, pulmonary vessels were partially included in the HAA values. However, the indices of fibrosis and emphysema that were obtained using the quantitative methods in our study reflected pulmonary function and were associated with hospitalization events.

Conclusion

In conclusion, objective quantitative CT measurements were significantly associated with the results of PFT and with the hospitalization of patients with CPFE. Quantitative CT measurements might serve as a useful method to determine the lung morphology, pathophysiology and clinical course of patients with CPFE.

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30 Jun 2020

PONE-D-20-02957

Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical events

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Reviewer #1: The study submitted by Masaki Suzuki et al. aims to evaluate the correlation between objective measurements of high-resolution chest CT and impaired pulmonary function, as well as clinical events in a prospective cohort of combined pulmonary fibrosis with emphysema (CPFE) patients. They found that the total abnormal area(%AA), %LAA and %HAA all correlated with decreased DLCO%predicted, %AA also showed a positive correlation with hospitalization, may have prognostic value.

In principle, the results are of interest for scientific and clinical community, deserved to be published, however I have some major concerns that prevent me to endorse its acceptance at the present stage.

1. The overall DLCO %predicted is 65.4 ± 23.3%, %LAA (median [IQR]) is only 4.9 (1.9 – 8.5) %. These two parameters reflect mild lung function impairment in this cohort. It is counterintuitive and does not go along with published data[1, 2], in which the DLCOs were usually severely reduced. I was wondering what is the participant recruitment strategy? (e.g., this research study only, patients with known pulmonary fibrosis and smoking history went on CT scanning, et al.) What is the source of potential biased selection?

2. Cardiac diseases especially heart failure should be added as exclusion criteria since lung edema would contribute to HAA value, add noise. Authors may carefully check if any patients with cardiac diseases had been enrolled in this study since 2 cases had been reported for hospitalization due to heart failure. It may be helpful to specify whether it is right-sided heart failure caused by chronic lung diseases.

3. Authors have defined -950 Hu as the threshold for low attenuation. It is adapted from Dr. Matsuoka’s study. However, 2mm slice thickness was used originally. Here using 0.5mm might have been too thin to measure LAA with a threshold setting of -950 Hu. It would overestimate emphysema[3]. Again, the %LAA in the entire cohort is around 5% with overestimation. The degree of emphysema makes negligible contribution to the lung function change. Therefore, it’s not surprising that no correlation found between %LAA with reduced LFT parameters and prognosis. Some of conclusions may due to bias.

1. Matsuoka, S., et al., Quantitative CT evaluation in patients with combined pulmonary fibrosis and emphysema: correlation with pulmonary function. Acad Radiol, 2015. 22(5): p. 626-31.

2. Ando, K., et al., Relationship between quantitative CT metrics and pulmonary function in combined pulmonary fibrosis and emphysema. Lung, 2013. 191(6): p. 585-91.

3. Gierada, D.S., et al., Effects of CT section thickness and reconstruction kernel on emphysema quantification relationship to the magnitude of the CT emphysema index. Acad Radiol, 2010. 17(2): p. 146-56.

Reviewer #2: I congratulate the authors for the research titled 'Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical event'. In the present study, CT findings and PFT values were compared in patients with CPFE, and the relationship between CT pathology (fibrozis and emphysema) and respiratory function loss was demonstrated. The research is very well organized and contributes to science in this regard. I think it can be published as it is.

Reviewer #3: 6/29/20

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Re: Manuscript Number: PONE-D-20-02957

Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical events

Dear Editorial team:

The authors present a manuscript entitled “Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical events.” The authors should be commended on their efforts to utilize CT attenuation values in patients with combined pulmonary fibrosis with emphysema (CPFE), and to correlate these values with pulmonary function test parameters (PFTs) and clinical outcomes. The authors demonstrate that in CPFE, increased total areas of low and high attenuation tissue (total abnormal area) did correlate with worse PFTs parameters and worse clinical outcomes. On the one hand, it is not surprising that patients with greater abnormalities on chest CT have greater impairment in PFTs and worse clinical outcomes, and potentially, the authors merely confirmed this commonly held belief. On the other hand, their approach to correlate CT attenuation values in CPFE patients with PFTs and clinical outcomes is relevant to patients if this technological approach is widely available in the clinical setting, and the authors also nicely present data assessing the specific contribution of low versus high attenuation areas on PFT parameters. The study is limited by the relatively small number of patients and the small number of patients developing adverse outcomes, but the authors do address these limitations well.

Minor concerns:

1) In the Methods and in Figure 1, the authors exclude 18 patients with connective tissue disease (CTD). I do understand that CTD likely has a different mechanism of disease than patients with idiopathic interstitial pneumonia (IIP), but it seems to me that assessing attenuation values in combined emphysema and fibrosis in patients with CTD would not be much different than assessing attenuation values in patients with IIP. If CTD patients were included, the number of patients studied would obviously be higher. Would be helpful if the authors could address their thoughts on the reasons for excluding these patients from analysis in the study.

2) It would be helpful if the authors would include the absolute numerical values for the PFT parameters in Table 1 (ie, measured values in liters [L] for spirometry and lung volumes, and measured values in ml CO/min/mm Hg for DLCO). Percent predicted values by definition depend upon prediction formulas and thus predicted values, which can be widely variable. It is interesting that the DLCO percent predicted values overall were not as low as I would have expected, and this may be merely related to the predicted values which were utilized in this study.

3) Mechanisms leading to centrilobular emphysema versus paraseptal emphysema in patients with CPFE may be different. Centrilobular emphysema is almost certainly a consequence of cigarette smoking, but paraseptal emphysema may occur merely as a manifestation of extensive intra-parenchymal fibrosis. Thus, centrilobular versus paraseptal emphysema may have differing effects on PFTs and clinical outcomes. I doubt this can be further assessed in this study given the relatively small number of patients in total overall, but perhaps the authors could include in their discussion regarding the differing etiologies of centrilobular versus paraseptal emphysema in patients with pulmonary fibrosis.

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19 Aug 2020

Reviewer #1

Comment 1

1. The overall DLCO %predicted is 65.4 ± 23.3%, %LAA (median [IQR]) is only 4.9 (1.9 – 8.5) %. These two parameters reflect mild lung function impairment in this cohort. It is counterintuitive and does not go along with published data[1, 2], in which the DLCOs were usually severely reduced. I was wondering what is the participant recruitment strategy? (e.g., this research study only, patients with known pulmonary fibrosis and smoking history went on CT scanning, et al.) What is the source of potential biased selection?

Response

- We appreciate your pointing this out. As you mentioned, the patients with CPFE are reported to show a significant reduction of DLCO, and the values for DLCO in our subjects were relatively preserved compared to previous studies [1, 2]. Our study was conducted in a single center. The study population was enrolled in accordance with the criteria of CPFE proposed by Cottin et al., which has pulmonary fibrosis and interstitial fibrosis on CT [1]. In the present study, we carefully checked smoking history and physical examination, as well as CT findings by 3 pulmonologists with 10, 15, and 20 years of experience. Similarly, Matsuoka et al. and Ando et al. used the same criteria of CPFE used by Cottin et al. Matsuoka et al. analyzed the CPFE patients with %LAA > 5% and Ando et al. investigated the study population after screening. Additionally, in the previous study, subclinical CPFE categorized by radiologists and biopsy-proven CPFE exhibited preserved pulmonary function, including DLCO [3]. In contrast, approximately 13% of patients with IPF with emphysema had emphysema lesions > 5% [4]. This study was a single-center study with a small number of enrolled patients, which may be a potential bias. We took the average of four CT slices to reflect the impact of fibrosis on pulmonary function in the inferior aspects of the lungs. The progression of abnormal lesions on chest CT might depend on the selected CT indices.

In recent reports, IPF subjects with preserved %VC received greater benefit from antifibrotic agents [5], and nintedanib reduced the decline in pulmonary function and acute exacerbation risk not only in patients with IPF, but also in patients with chronic fibrosing ILDs [6, 7]. These data provide the possibility for CPFE patients with mild-to-moderate pulmonary dysfunction to respond to novel treatments. To confirm the verification of our study without a lower limit of %LAA, a multicentric cohort study is warranted.

We added study limitations as below.

In the Discussion section, lines 359–361:

“First, this was a single-center study with a small number of enrolled patients and the pulmonary function of the subjects was preserved compared to previous studies [1, 4, 6, 12].”

Comment 2

2. Cardiac diseases especially heart failure should be added as exclusion criteria since lung edema would contribute to HAA value, add noise. Authors may carefully check if any patients with cardiac diseases had been enrolled in this study since 2 cases had been reported for hospitalization due to heart failure. It may be helpful to specify whether it is right-sided heart failure caused by chronic lung diseases.

Response 2

- We appreciate your comment. As the reviewer pointed out, cardiac diseases, particularly cognitive heart failure, may affect values for HAA. We reviewed the cardiac status backgrounds in all our subjects at the time of enrollment. No subjects developed heart failure or pneumonia at the time of enrollment. In addition, no CT slices showed abnormal findings associated with pulmonary edema, such as ground glass opacity, bronchovascular bundle thickening with a central distribution and sparing of the lung cortex, and pleural effusion. In this study, two subjects developed heart failure due to old myocardial infarctions during the follow-up period. Unfortunately, because the two subjects were not examined with pulmonary artery catherization at the time of hospitalization, we could not conclude whether right- or left-sided heart failure was associated with chronic lung disease.

We revised the manuscript as below.

In the Materials and methods section, lines 108–109:

“6) chemotherapy (n = 2); 7) heart failure (n = 0); and 8) others (n = 14).”

In the Results section, lines 237–238:

“bacterial pneumonia (n = 2), heart failure due to an old myocardial infarction (n = 2),”

Comment 3

3. Authors have defined -950 Hu as the threshold for low attenuation. It is adapted from Dr. Matsuoka’s study. However, 2mm slice thickness was used originally. Here using 0.5mm might have been too thin to measure LAA with a threshold setting of -950 Hu. It would overestimate emphysema [3]. Again, the %LAA in the entire cohort is around 5% with overestimation. The degree of emphysema makes negligible contribution to the lung function change. Therefore, it’s not surprising that no correlation found between %LAA with reduced LFT parameters and prognosis. Some of conclusions may due to bias.

Response 3

- We appreciate your comments regarding CT slice thickness. We adopted a 0.5 mm thickness on CT for morphological evaluation in our previous reports [8-10]. Although CT images with various thicknesses (1–2.5 mm) were used for quantitative CT assessment [11-13], we adopted the same organized slice thickness for all subjects. We evaluated the correlation between the values obtained with 0.5 and 2 mm CT slice thicknesses. We prepared 2-mm thickness data stacked for the study population using ImageJ (https://imagej.net/Fiji). The %LAA and %HAA from the 2-mm CT thickness were calculated using the same method. The median (IQR) %LAA and %HAA from the 0.5- and 2-mm CT thicknesses were as follows: %LAA, 4.9 % (1.9–8.5) versus 4.7 % (1.7–8.4); and %HAA, 20.2 % (15.4–25.6) versus 19.4 % (15.4–25.6). The ICC of %LAA and %HAA between the 0.5- and 2-mm CT slice thicknesses were as follows: %LAA, 0.9993 (95% CI, 0.9987–0.9996); and %HAA, 0.9969 (0.9946–0.9983). The %LAA from the 0.5-mm thickness was larger than that from the 2-mm thickness. The coefficient values for both %LAA and %HAA were high. As pointed out, the slice thickness and the reconstruction kernel are quite important to perform quantitative measurements for imaging analysis. We plan to elucidate this point in a corollary study.

Reviewer #2

Comment

I congratulate the authors for the research titled 'Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical event'. In the present study, CT findings and PFT values were compared in patients with CPFE, and the relationship between CT pathology (fibrozis and emphysema) and respiratory function loss was demonstrated. The research is very well organized and contributes to science in this regard. I think it can be published as it is.

Response

- We greatly appreciate your helpful and encouraging comments. The pathogenesis and physiological findings are distinct in patients with CPFE, thus targeted antifibrotic therapy might be needed. We consider that larger clinical trials on CPFE are required to elucidate the relationship between pulmonary function, radiological characteristics, and clinical course.

Reviewer #3

Comment 1

1) In the Methods and in Figure 1, the authors exclude 18 patients with connective tissue disease (CTD). I do understand that CTD likely has a different mechanism of disease than patients with idiopathic interstitial pneumonia (IIP), but it seems to me that assessing attenuation values in combined emphysema and fibrosis in patients with CTD would not be much different than assessing attenuation values in patients with IIP. If CTD patients were included, the number of patients studied would obviously be higher. Would be helpful if the authors could address their thoughts on the reasons for excluding these patients from analysis in the study.

Response 1

- We appreciate your comments regarding CPFE with CTD. Compared to CPFE patients without CTD, CPFE patients with CTD were more often female gender, had deteriorated pulmonary function, pulmonary hypertension, and a poor prognosis [14, 15]. The mechanism of underlying CPFE with CTD might differ from that of patients with CPFE but without CTD and might be of clinical interest in clinical practice. Regarding clinical events, CPFE patients with CTD could have exacerbations and require hospitalization due to extra-pulmonary complications and treatment (immunosuppressants and/or steroids)-related side effects or infections. Thus, in focus on the relationship between CT assessments and clinical events of patients with CPFE but without CTD, we excluded CPFE patients with CTD in this study. We plan to investigate the differences between CPFE patients with or without CTD in a corollary study.

Comment 2

2) It would be helpful if the authors would include the absolute numerical values for the PFT parameters in Table 1 (ie, measured values in liters [L] for spirometry and lung volumes, and measured values in ml CO/min/mm Hg for DLCO). Percent predicted values by definition depend upon prediction formulas and thus predicted values, which can be widely variable. It is interesting that the DLCO percent predicted values overall were not as low as I would have expected, and this may be merely related to the predicted values which were utilized in this study.

Response 2

- We appreciate your comment. We revised Table 1 as below, including absolute numerical values for FVC, TLC, and DLCO. The absolute numerical values among our subjects were also lower than previous studies [1, 2, 4]; however, we enrolled the study population in accordance with the criteria of CPFE, as proposed by Cottin et al. [1]. Similarly, Matsuoka et al. and Ando et al. used the same criteria for CPFE. Matsuoka et al. analyzed CPFE patients with a %LAA > 5% and Ando et al. investigated the study population after screening. In contrast, approximately 13% of patients with IPF and emphysema had emphysema lesions > 5% [4]. The inclusion criteria might affect the pulmonary function differences in the study population. We plan to investigate the relationships between CT assessments and clinical courses in a multicentric cohort, including progressed CPFE subjects.

We revised Table 1 as below and the Supplemental file.

In the Results section, lines 188–189:

Table 1. Patient characteristics, pulmonary function tests, and computed tomography measurements

Mean ± SD

Age (years) 67.2 ± 7.8

Male/female, n (%) 45 (97.8 %)/1 (2.2 %)

BMI (kg/m2) 24.0 ± 3.7

Pack years 62.0 ± 41.2

Smoker (Current or ever/never) 45 (97.8 %)/1 (2.2 %)

Follow-up duration (days) 1087.9 ± 574.5

KL-6 (U/mL) 1038.8 ± 1041.0

Pulmonary function tests

FVC (L) 3.1 ± 0.8

FVC %predicted (%) 86.7 ± 20.3

FEV1 %predicted (%) 81.8 ± 18.3

FEV1/FVC (%) 77.9 ± 9.3

FRC %predicted (%) 81.8 ± 16.6

RV %predicted (%) 83.3 ± 21.2

TLC (L) 4.7 ± 1.0

TLC %predicted (%) 84.3 ± 15.9

DLCO (mL/min/mmHg) 11.7 ± 4.6

DLCO %predicted (%) 65.4 ± 23.3

CT measurements

Emphysema type (centrilobular/paraseptal/mixed type) 21/17/8

Fibrosis type (UIP/probable UIP/indeterminate for UIP/alternative diagnosis pattern) 15/19/10/2

%LAA (median [IQR]) (%) 4.9 (1.9 – 8.5)

%HAA (median [IQR]) (%) 20.2 (15.4 – 25.6)

%AA (median [IQR]) (%) 25.5 (21.0 – 36.2)

Clinical events

Hospitalization, n (%) 8 (17.4 %)

Acute exacerbation, n (%) 2 (4.3 %)

Death, n (%) 3 (6.5 %)

Comment 3

3) Mechanisms leading to centrilobular emphysema versus paraseptal emphysema in patients with CPFE may be different. Centrilobular emphysema is almost certainly a consequence of cigarette smoking, but paraseptal emphysema may occur merely as a manifestation of extensive intra-parenchymal fibrosis. Thus, centrilobular versus paraseptal emphysema may have differing effects on PFTs and clinical outcomes. I doubt this can be further assessed in this study given the relatively small number of patients in total overall, but perhaps the authors could include in their discussion regarding the differing etiologies of centrilobular versus paraseptal emphysema in patients with pulmonary fibrosis.

Response 3

- We appreciate that you have pointed this out. Conventionally, emphysema is categorized into three types: centrilobular, paraseptal, and panlobular [16]. Centrilobular emphysema is characterized by low attenuation surrounded by normal attenuation located within the central portion of the pulmonary lobules. In contrast, paraseptal emphysema is characterized by low attenuation adjacent to subpleural and peribronchovascular areas. Centrilobular emphysema is commonly complicated by smoking, which is consistent with the finding that COPD patients often have centrilobular emphysema [17]. In addition, the emphysema subtypes are reportedly related to pulmonary symptoms, the development of lung cancer, and worsening radiological findings in patients with COPD [18, 19]. In contrast, CPFE patients frequently (30%-65%) exhibit paraseptal emphysema [2, 20], and CPFE with paraseptal emphysema is reportedly associated with CTD and a poor prognosis [14, 15, 21]. Similarly, our study population included 17 subjects (34%) with paraseptal emphysema, which is consistent with previous studies [2, 20]. Because our sample size was small, we could not perform a sub-group analysis in this study. We plan to investigate the relationship between emphysema types in combination with quantitative HRCT assessments in CPFE patients.

We revised the manuscript as below.

In the Discussion section, lines 300–306:

“Emphysema subtypes are divided into three types; centrilobular, paraseptal, and panlobular [24]. Centrilobular emphysema is commonly complicated by COPD [25], and emphysema subtypes in COPD are related to pulmonary symptoms, the development of lung cancer, and worsening radiological findings [26, 27]. In contrast, CPFE patients are likely to exhibit paraseptal emphysema (30%-65%) [28, 29], which is consistent with the present study. CPFE with paraseptal emphysema lesions is associated with CTD and a poor prognosis [30-32]. Considering emphysema subtypes in CPFE might contribute to the putative clinical course.”

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21. Todd NW, Jeudy J, Lavania S, Franks TJ, Galvin JR, Deepak J, et al. Centrilobular emphysema combined with pulmonary fibrosis results in improved survival. Fibrogenesis & tissue repair. 2011;4(1):6. Epub 2011/02/18. doi: 10.1186/1755-1536-4-6. PubMed PMID: 21324139; PubMed Central PMCID: PMCPMC3055815.

Submitted filename: Response to Reviewers.docx

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31 Aug 2020

Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical events

PONE-D-20-02957R1

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Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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Reviewer #3: Yes

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Reviewer #3: Yes

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Reviewer #1: (No Response)

Reviewer #3: Yes

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Reviewer #3: Yes

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Reviewer #1: No

Reviewer #3: No

3 Sep 2020

PONE-D-20-02957R1

Objective quantitative multidetector computed tomography assessments in patients with combined pulmonary fibrosis with emphysema: relationship with pulmonary function and clinical events

Dear Dr. Suzuki:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Kind regards,

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on behalf of

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Academic Editor

PLOS ONE