
==== Front
Intern Med
Intern Med
Internal Medicine
0918-2918
1349-7235
The Japanese Society of Internal Medicine

38171859
10.2169/internalmedicine.2250-23
Original Article
A Quantitative Computed Tomography Analysis of Fissure Integrity and Emphysema Destruction in Japanese Patients with Severe Chronic Obstructive Pulmonary Disease
Mineshita Masamichi 1
Nishine Hiroki 1
Handa Hiroshi 1
Kida Hirotaka 1
Inoue Takeo 1
1 Department of Respiratory Medicine, St. Marianna University School of Medicine, Japan
Correspondence to Dr.　Masamichi Mineshita, m-mine@marianna-u.ac.jp

2 1 2024
15 8 2024
63 16 22692275
15 5 2023
13 11 2023
Copyright © 2024 by The Japanese Society of Internal Medicine
https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Objective

Bronchoscopic lung volume reduction (BLVR) using a one-way endobronchial valve (EBV) can provide clinically meaningful benefits to chronic obstructive pulmonary disease (COPD) patients. Although the Japanese Pharmaceuticals and Medical Devices Agency approved EBVs in November 2022, information regarding the number of Japanese patients with severe COPD eligible for BLVR treatment is still lacking. We therefore screened computed tomography (CT) images of patients with severe COPD using a quantitative CT (QCT) analysis to estimate the proportion of candidates eligible for BLVR treatment with an EBV.

Methods

CT scans of COPD patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4 were retrospectively analyzed using QCT to evaluate fissure integrity and tissue destruction. The difference in volume-weighted percentage was measured using the density scores of the target lobe and ipsilateral non-target lobe at -910 Hounsfield units. The target lobe was defined as the most affected lobe, with an emphysema destruction score of ＞50% for each patient.

Results

High-resolution CT scans of 32 patients (GOLD 3=19, GOLD 4=13) were analyzed. The target lobe could not be identified in 1 patient, whereas the target lobes for 8 patients were not surrounded by fissures with ≥80% completeness. Conversely, in 13 patients, the target lobes were surrounded by fissures with ＞95% completeness. The remaining 10 patients had fissure completeness between 80% and 95% at the target lobes and were considered candidates for collateral ventilation assessment.

Conclusion

A QCT analysis showed that 23 of 32 patients with severe COPD could be considered for a thorough examination of BLVR treatment with EBV.

bronchoscopic lung volume reduction (BLVR)
emphysema
quantitative CT (QCT) analysis
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pmcIntroduction

In patients with severe chronic obstructive pulmonary disease (COPD), disease management strategies, such as pharmacological therapies, smoking cessation, pulmonary rehabilitation, and long-term oxygen therapy, can be introduced to improve exercise tolerance and the quality of life (QOL). However, despite optimal medical management, most patients with severe COPD remain significantly disabled.

Although surgical approaches, such as lung transplantation and lung volume reduction surgery (LVRS), have shown improvements in the pulmonary function and QOL, a shortage of donor organs, various postoperative complications, and the cost of healthcare are important limiting factors (1,2).

Bronchoscopic lung volume reduction (BLVR) is a relatively low invasive treatment option (3,4). BLVR using one-way endobronchial valves (EBVs), can provide clinically meaningful benefits. The US Food and Drug Administration has approved two types of valve systems, and Global Initiative for Chronic Obstructive Lung Disease (GOLD)-COPD has adopted a one-way EBV as a treatment for patients with advanced emphysema (5). These valves block airflow on inspiration to the target lobe while permitting secretions and air from the lobe during expiration. EBVs have shown improvements in the pulmonary function, exercise capacity, and symptoms in patients with severe heterogeneous and hyper-inflated emphysema (6,7).

Although a certain amount of emphysematous destruction of the target lobe is necessary to obtain clinical benefit with these valves, the most important factor for this treatment is the absence of interlobar collateral ventilation (CV) (3,4). The Chartis SystemⓇ (Pulmonx, Redwood City, USA) can measure CV directly, while computed tomography (CT) is used as an indirect assessment of CV. Koster et al. reported an indication for interlobar pleural integrity using quantitative computed tomography (QCT) (8). Patients with fissures with ≥80% completeness can be treated for further analyses and/or treatment with an EBV. Patients with a fissure completeness of ＜80% are not considered for EBV treatment. If a QCT analysis shows a fissure completeness between 80% and 95%, a Chartis measurement should be performed to confirm the absence of CV. If the fissure completeness is ＞95%, EBV treatment can be delivered directly (8).

The Japanese Pharmaceuticals and Medical Devices Agency has approved the use of EBVs since November 2022, and BLVR using EBV will soon be available for clinical use in Japan. However, there is currently a lack of information on the proportion of COPD patients who will be eligible for this treatment. Therefore, we screened CT images of patients with severe COPD using QCT to determine the number of patients eligible for a thorough examination of BLVR treatment with an EBV.

Materials and Methods

Patients in this study were selected from a prospective registry of chronic respiratory diseases. This prospective registry study of chronic respiratory diseases was performed at St. Marianna University Hospital, and written informed consent was obtained from all participants. This study was approved by the ethics committee of our institution (approval number: 3182) (Approval date: February 5, 2016; Approval of changes: April 26, 2021).

Among the reviewed patients, 35 with severe but stable COPD (GOLD 3 and 4) were identified at the time of enrollment and follow-up. Three patients were excluded: one due to post-lung resection, one due to post-tuberculosis sequelae, and one due to post-inflammatory changes of bilateral pneumonia. High-resolution CT (HRCT) scans of these patients were retrospectively analyzed using the StratXⓇ Lung Analysis Platform (PulmonX, Redwood City, USA). This software program is a cloud-based QCT analysis service that provides information on emphysema destruction, fissure completeness, and lobar volume.

Homogeneous emphysema was defined as a ＜15% difference in the emphysema destruction score (EDS) between the target and ipsilateral lobes (7). The difference in volume-weighted percentage was measured using the density scores of the target lobe and ipsilateral nontarget lobe at -910 and -950 Hounsfield units (7,9). In this study, the target lobe was defined as the most affected lobe with ＞50% EDS at -910 Hounsfield units (EDS-910) or ＞30% EDS at -950 Hounsfield units (EDS-950) for each patient (9). Eligibility for a thorough examination for BLVR treatment with an EBV was determined based on fissure completeness and EDS data at -910 Hounsfield units.

Results

The HRCT scans of 32 patients with severe COPD (GOLD 3=19, GOLD 4=13) were analyzed. Patient characteristics are shown in Table 1. The mean age and FEV1% were 72.6 years old and 34.2%, respectively, and 27 patients were men.

Table 1. Characteristics of Subjects.

Subjects	32 (male=27)	
Age (years)	72.6±6.9	
Pulmonary function tests		
FVC%predicted	79.8±17.0 %	
FEV1%predicted	33.4±11.9 %	
FEV1/FVC (%)	34.2±6.6 %	
GOLD 3	19	
GOLD 4	13	
FVC: forced vital capacity, FEV1: forced expiratory volume in 1 second, GOLD: Global Initiative for Chronic Obstructive Lung Disease (GOLD 3 - severe; GOLD 4 - very severe)

Values are represented as mean±standard deviation.

The average fissure completeness, EDS-910, and EDS-950 for each lobe are listed in Table 2. The median fissure integrity was 91.8% for the right major fissure and 89.3% for the left major fissure. The fissure completeness of the right upper and middle lobes was 82.3% and 86.9%, respectively. The EDS-910 of each lobe was above 60%, with slightly higher results for both upper lobes. The EDS-950 of each lobe was above 50.0%, with slightly higher results for both upper lobes.

Table 2. Average Fissure Completeness, EDS-910 and EDS-950 of Each Lobe.

	RUL	RML	RLL	LUL	LLL	
%fissure completeness	82.3±16.5%	86.9±10.2%	91.8±10.9%	89.3±14.1%	89.2±14.1%	
EDS-910	67.4±8.8%	66.0±9.6%	65.6±10.8%	66.1±8.1%	62.3±11.3%	
EDS-950	55.0±9.6%	50.1±13.8%	53.6±11.5%	53.4±8.5%	50.0±11.4%	
EDS-910: emphysema destruction score at -910 Hounsfield units, EDS-950: emphysema destruction score at -950 Hounsfield units, LLL: left lower lobe, LUL: left upper lobe, RLL: right lower lobe, RML: right middle lobe, RUL: right upper lobe

Values are represented as means±standard deviation.

Of the 32 patients, 6 were defined as having heterogeneous emphysema. The target lobe was not found in one patient with homogeneous emphysema (case 3) using EDS -910, although the target lobes were present at EDS-950 in all patients (Table 3).

In 8 patients (cases 2, 9, 10, 12, 17, 21, 27, and 29), there were no surrounding fissures with ≥80% completeness at the target lobes (Table 4). We therefore deemed these patients were unsuitable for EBV treatment. In contrast, in 13 patients (cases 4, 5, 8, 15, 16, 18, 20, 22-26, and 32), the most damaged lobes were surrounded by fissures of ＞95% completeness and were considered appropriate candidates for EBV placement by a QCT analysis. The remaining 10 patients had target lobes with 80-95% fissure completeness and were considered candidates for a CV assessment.

Table 3. EDS and Emphysema Type of Each Patient.

EDS-910	
Cases	GOLD stage	EDS-910 (%)	Emphysema type	
RUL	RML	RLL	LUL	LLL	
1	4	76	72	75	71	64	Homogeneous	
2	4	77	76	75	80	74	Homogeneous	
3	3	48	50	38	47	41	Homogeneous	
4	4	71	71	77	69	72	Homogeneous	
5	3	69	69	71	69	69	Homogeneous	
6	3	73	75	67	72	73	Homogeneous	
7	3	61	69	60	61	47	Homogeneous	
8	3	76	66	57	63	52	Heterogeneous	
9	3	73	44	49	70	56	Heterogeneous	
10	3	63	53	54	60	58	Homogeneous	
11	3	75	79	66	68	57	Homogeneous	
12	4	75	76	82	75	76	Homogeneous	
13	4	58	82	72	75	70	Heterogeneous	
14	3	82	52	80	63	42	Heterogeneous	
15	4	59	59	51	60	67	Homogeneous	
16	4	63	69	74	61	68	Homogeneous	
17	3	75	75	69	71	51	Homogeneous	
18	3	62	63	71	64	61	Homogeneous	
19	3	51	47	44	49	42	Homogeneous	
20	3	70	70	66	70	65	Homogeneous	
21	3	78	61	65	71	62	Heterogeneous	
22	3	60	67	63	62	61	Homogeneous	
23	4	67	74	76	76	82	Homogeneous	
24	3	61	67	69	64	67	Homogeneous	
25	4	69	63	65	69	65	Homogeneous	
26	3	64	70	64	71	65	Homogeneous	
27	3	68	70	70	68	72	Homogeneous	
28	3	48	55	57	46	50	Homogeneous	
29	3	70	56	54	58	44	Heterogeneous	
30	4	64	70	62	72	70	Homogeneous	
31	4	75	70	78	69	69	Homogeneous	
32	4	75	71	78	73	80	Homogeneous	
	
EDS-950	
Case	GOLD stage	EDS-950 (%)	Emphysema type	
RUL	RML	RLL	LUL	LLL	
1	4	66	60	65	60	52	Homogeneous	
2	4	65	62	62	69	62	Homogeneous	
3	3	32	34	26	32	29	Homogeneous	
4	4	58	58	68	57	61	Homogeneous	
5	3	55	54	59	56	56	Homogeneous	
6	3	59	61	54	58	59	Homogeneous	
7	3	48	57	49	48	36	Homogeneous	
8	3	63	49	42	48	39	Heterogeneous	
9	3	63	30	38	58	44	Heterogeneous	
10	3	50	39	41	47	45	Homogeneous	
11	3	63	67	53	54	43	Homogeneous	
12	4	64	62	71	62	64	Homogeneous	
13	4	45	72	61	64	58	Heterogeneous	
14	3	74	39	73	50	31	Heterogeneous	
15	4	46	45	40	48	55	Homogeneous	
16	4	51	55	63	48	57	Homogeneous	
17	3	62	61	56	58	38	Homogeneous	
18	3	49	49	59	52	50	Homogeneous	
19	3	37	32	30	34	29	Homogeneous	
20	3	55	52	50	55	48	Homogeneous	
21	3	69	47	53	61	51	Heterogeneous	
22	3	49	53	51	50	49	Homogeneous	
23	4	57	64	66	66	72	Homogeneous	
24	3	50	55	58	52	56	Homogeneous	
25	4	56	48	52	55	52	Homogeneous	
26	3	50	54	51	58	51	Homogeneous	
27	3	52	52	56	52	57	Homogeneous	
28	3	37	44	46	37	39	Homogeneous	
29	3	58	40	41	46	32	Heterogeneous	
30	4	51	57	50	59	57	Homogeneous	
31	4	62	55	66	55	56	Homogeneous	
32	4	64	57	67	60	70	Homogeneous	
EDS-910: emphysema destruction score at -910 Hounsfield units, EDS-950: emphysema destruction score at -950 Hounsfield units, GOLD: Global Initiative for Chronic Obstructive Lung Disease (GOLD 3 - severe; GOLD 4 - very severe), LLL: left lower lobe, LUL: left upper lobe, RLL: right lower lobe, RML: right middle lobe, RUL: right upper lobe

Cells with grey backgrounds; defined target lobes.

Table 4. Fissure Completeness at -910 Hounsfield Units and Assessment of Treatment in Each Patient.

Cases	Fissure completeness	Assessment	
RUL	RML	RLL	LUL	LLL	
1	86.9	93.5	94.2	95.9	95.9	CV analysis	
2	100.0	93.4	92.6	73.8	73.8	Incomplete fissure	
3	94.3	93.5	98.2	78.2	78.2	No target lobes	
4	100.0	100.0	100.0	96.7	96.7	EBV placement	
5	97.7	98.3	100.0	90.2	90.2	EBV placement	
6	95.0	93.1	98.9	100.0	100.0	CV analysis	
7	90.4	93.2	99.4	100.0	100.0	CV analysis	
8	98.0	100.0	98.0	100.0	100.0	EBV placement	
9	69.4	89.8	65.6	76.6	76.6	Incomplete fissure	
10	68.1	72.6	95.9	93.7	93.7	Incomplete fissure	
11	90.8	86.4	98.3	94.5	94.5	CV analysis	
12	37.4	66.7	58.9	55.0	55.0	Incomplete fissure	
13	88.3	89.6	97.6	93.6	93.6	CV analysis	
14	82.9	80.6	94.0	91.1	91.1	CV analysis	
15	52.6	64.5	87.9	97.6	97.6	EBV placement	
16	89.2	93.7	100.0	100.0	100.0	EBV placement	
17	68.6	73.7	83.4	51.3	51.3	Incomplete fissure	
18	89.5	90.6	98.3	100.0	100.0	EBV placement	
19	83.6	87.7	98.1	97.3	97.3	CV analysis	
20	75.5	81.4	100.0	96.9	96.9	EBV placement	
21	57.5	74.8	68.8	100.0	100.0	Incomplete fissure	
22	98.6	98.3	99.0	98.1	98.1	EBV placement	
23	83.5	84.7	100.0	100.0	100.0	EBV placement	
24	97.0	94.2	95.7	92.7	92.7	EBV placement	
25	100.0	96.4	96.3	100.0	100.0	EBV placement	
26	75.1	81.4	100.0	96.7	96.7	EBV placement	
27	91.4	94.3	94.2	74.6	74.6	Incomplete fissure	
28	84.6	95.5	87.2	82.0	82.0	CV analysis	
29	63.3	77.8	74.3	55.2	55.2	Incomplete fissure	
30	53.5	66	82.9	82.7	82.7	CV analysis	
31	100.0	89.8	90.3	92.0	92.0	CV analysis	
32	70.4	84.1	89.7	100.0	100.0	EBV placement	
LLL: left lower lobe, LUL: left upper lobe, RLL: right lower lobe, RML: right middle lobe, RUL: right upper lobe, CV: collateral ventilation, EBV: endobronchial valve

Cells with grey backgrounds; defined target lobes.

Fig. 1 shows the CT images of Case 8. This case showed heterogeneous emphysema with a right upper lobe EDS-910 of 76% and a right lower lobe EDS-910 of 57%. Fissure integrity was 98.0% for the right major fissure, and 100% for the left major fissure. This case was considered suitable for right upper lobe obstruction using an EBV. Fig. 2 shows the CT images for Case 12. In this case, homogeneous emphysema with an EDS-910 of 75-82% was observed for each lobe. Fissure integrity was 58.9% for the right major fissure, and 55.0% for the left major fissure. This case was considered unsuitable for BLVR with an EBV because of fissure incompleteness.

Figure 1. CT images of case 8. This case showed heterogeneous emphysema with a right upper lobe EDS-910 of 76% and a left lower lobe EDS-910 of 52%. Fissure integrity was 98.0% for the right major fissure and 100% for the left major fissure. This case was considered suitable for right upper lobe obstruction using EBV.

Figure 2. CT images for case 12. This case was homogeneous emphysema with an EDS-910 of 75% to 82% for each lobe. The fissure integrity was 58.9% for the right major fissure and 55.0% for the left major fissure. This case was considered unsuitable for BLVR with an EBV (yellow arrowheads indicate incomplete interlobar fissure).

Discussion

We found for the first time that approximately 70% of Japanese patients with severe COPD were eligible for a thorough examination to determine the EBV indication, although the percentage of these patients receiving BLVR with an EBV remains to be elucidated.

In patients with severe emphysema, BLVR with an EBV can significantly improve the exercise tolerance, pulmonary function, and QOL. Interlobar integrity and advanced destruction of the target lung lobe are important indications for this treatment, and QCT is used to evaluate fissure integrity and tissue destruction (4,8). To obtain a clinical benefit, a certain degree of emphysematous destruction is required. The percentage of low-attenuation areas must be ＞50% at -910 Hounsfield units or ＞30% at -950 Hounsfield units (9). In the present study, the EDS was calculated at -910 Hounsfield units, as used in the LIBERATE study (7). We found that 31 of 32 patients had sufficient emphysema destruction in their target lobes. We also evaluated EDS at -950 Hounsfield units and found that all patients had lobes with values of ≥30%. Since it has been reported that 90% of Japanese patients with COPD suffer from emphysema-dominant lung disease (10), most patients with severe COPD are likely to have sufficient emphysematous lesions for EBV indication, which is consistent with the present study.

According to a recent report, interlobar pleural integrity is genetically determined and independent of factors such as age, sex, or smoking status (11). The median fissure integrity in that report was 97.9% for the left major fissure, 92.7% for the right major fissure, and 72.2% for the right minor fissure at baseline, with African Americans having a significantly higher fissure completeness than non-Hispanic whites for all 3 fissure locations. The fissure completeness in our patients was 89.2% for the left major fissure and 91.8% for the right major fissure. Although the left major fissure integrity was lower in our patients than in the aforementioned previous study, a further evaluation with more cases is needed to determine whether or not this difference is due to race.

Although the target lobe in the present study was defined as one lung lobe, combining the right upper lobe and right middle lobes can be considered if collateral flow is present across the minor fissure (9). For example, 6.3% of cases were treated for the right upper and right middle lobes simultaneously in the LIBERATE study (7). Therefore, if both the right upper and middle lobes are considered for treatment, then case 10, whose integrity at the right major fissure was ＞95%, could be considered a viable candidate for EBV placement, while case 17, whose integrity at the right major fissure was 83.4%, could be considered a candidate for a CV analysis. We conclude that these two cases could be potential candidates for this treatment.

Klooster et al. reported that stricter criteria should be used for the right major fissure than the left major fissure (12). They argued that patients with ＜80% completeness of the left major fissure or ＜90% completeness of the right major fissure could be excluded from CV evaluation and EBV treatment. In our study, case 28 would have been excluded by applying Klooster's criteria; however, approximately 70% of our cases would have been indicated for EBV treatment according to QCT findings. Additional factors must also be considered when selecting a target lesion. The ideal target lobe for one-way valve treatment is characterized by the highest emphysema heterogeneity, and air trapping, and lowest perfusion (9). Indeed, patient selection should be based on not only a QCT evaluation but also the history of COPD treatment, comorbidities, and various other conditions (4,9).

Of note, it has been reported that only 20% of patients referred for BLVR treatment are actually eligible for BLVR treatment (13). Welling et al. retrospectively reviewed 1,500 patients referred for BLVR and found that only 545 patients were considered eligible for EBV treatment based on pulmonary function tests (13). Of these 545 patients, 378 had intact major fissures as visually assessed by HRCT, and of whom 283 patients had emphysematous destruction rated ≥2 on the Likert scale (0 to 4 qualitative scale with higher scores indicating more emphysematous destruction). According to that report, 51.9% of the 545 patients were considered eligible for EBV.

However, their population was a group of patients referred to a BLVR center and was not representative of the total population. Furthermore, the HRCT analysis was based on a visual assessment. Although the current study is a single-center study with a small sample size, we believe that it is valuable as a pilot study for examining the number of Japanese patients with severe COPD who could be candidates for EBV. Future multicenter studies with more cases are required to confirm the results of this study.

Conclusion

Although this study was conducted at a single institution and involved a small number of cases, we discovered for the first time that a significant proportion of Japanese patients with severe COPD could be eligible for a thorough examination to determine EBV indication.

Author's disclosure of potential Conflicts of Interest (COI).

Masamichi Mineshita: Honoraria, Pulmonx Japan.

Acknowledgement

The authors would like to thank Mr. Jason Tonge for his assistance in preparing this manuscript. The authors would also like to thank Pulmonx for their support with the QCT analysis. This abstract was published in a thematic poster session in the European Respiratory Journal 2020; 56: Suppl. 64, 880. Hyperlink: https://erj.ersjournals.com/content/56/suppl_64/880.
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