Relationships Between High-Resolution Computed Tomographic Features and Lung Function Trajectory in Patients With Asthma

Abstract

Purpose

A subset of asthmatics suffers from persistent airflow limitation, known as remodeled asthma, despite optimal treatment. Typical quantitative scoring methods to evaluate structural changes of airway remodeling on high-resolution computed tomography (HRCT) are time-consuming and laborious. Thus, easier and simpler methods are required in clinical practice. We evaluated the clinical usefulness of a simple, semi-quantitative method based on 8 HRCT parameters by comparing asthmatics with a persistent decline of post-bronchodilator (BD)-FEV1 to those with a BD-FEV1 that normalized over time and evaluated the relationships of the parameters with BD-FEV1.

Methods

Asthmatics (n = 59) were grouped into 5 trajectories (Trs) according to the changes of BD-FEV1 over 1 year. After 9–12 months of guideline-based treatment, HRCT parameters including emphysema, bronchiectasis, anthracofibrosis, bronchial wall thickening (BWT), fibrotic bands, mosaic attenuation on inspiration, air-trapping on expiration, and centrilobular nodules were classified as present (1) or absent (0) in 6 zones.

Results

The Tr5 group (n = 11) was older and exhibited a persistent decline in BD-FEV1. The Tr5 and Tr4 groups (n = 12), who had a lower baseline BD-FEV1 that normalized over time, had longer durations of asthma, frequent exacerbations, and higher doses of steroid use compared to the Tr1–3 groups (n = 36), who had a normal baseline BD-FEV1. The Tr5 group had higher emphysema and BWT scores than the Tr4 (P = 8.25E-04 and P = 0.044, respectively). Scores for the other 6 parameters were not significantly different among the Tr groups. BD-FEV1 was inversely correlated with the emphysema and BWT scores in multivariate analysis (P = 1.70E-04, P = 0.006, respectively).

Conclusions

Emphysema and BWT are associated with airway remodeling in asthmatics. Our simple, semi-quantitative scoring system based on HRCT may be an easy-to-use method for estimating airflow limitation.

INTRODUCTION

Asthma is a heterogeneous disease characterized by various degrees of airway inflammation and an inconsistent response to treatment with inhaled corticosteroids (ICSs). In most asthmatic patients asthma control and normal lung function can be achieved with medications.¹ However, a subset of asthmatics experience progressive airflow limitation due to frequent exacerbations and persistent airway inflammation despite optimal treatment.²,³ The rapid decline in airflow rate is associated with greater morbidity and mortality in severe asthmatics.⁴,⁵,⁶,⁷ Therefore, early identification of risk factors for ongoing deterioration of airway function is essential for asthma management. Previously, we investigated clinical and inflammatory factors related to persistent airflow limitation, based on changes of post bronchodilator (BD)-forced expiratory volume in 1 second (FEV1) (% pred.) in 1,679 asthmatics who were followed every 3 months for 1 year.⁸ Cluster analysis identified 5 distinct trajectories (Trs): the Tr1–3 groups had a normal BD-FEV1 (% pred.) at baseline, while the Tr4 and Tr5 groups had severe asthma with a marked reduction of baseline BD-FEV1 (% pred.). The BD-FEV1 (% pred.) of the Tr4 group was restored to normal after 3–6 months of treatment, whereas the Tr5 group exhibited persistently disturbed BD-FEV1 (% pred.) despite 1 year of treatment. The decline in BD-FEV1 is closely related to narrowing of the airways, in turn caused by a loss of elasticity of the structural wall due to remodeling and persistent inflammation.⁹ Structural changes in the airways and lung parenchyma have been evaluated using imaging modalities, particularly high-resolution computed tomography (HRCT).¹⁰,¹¹

HRCT enables the assessment of static and dynamic changes in the airways and lung parenchyma at multiple levels.¹¹,¹² The lung airways consist of cartilaginous, membranous, and gas-exchanging bronchi, including the respiratory bronchioles and alveolar ducts. The large to medium sized bronchi are the main contributors to airway resistance, which is functionally reflected in FEV1 and forced mid-expiratory flow.¹³ Bronchial wall thickening (BWT), mucus impaction, mosaic attenuation on expiration, emphysema, and atelectasis are only detectable on HRCT.¹⁴ These abnormalities are observed in up to 80% of asthmatics,¹⁵,¹⁶ and are more prominent in those with FEV1 decline and longer-duration asthma.¹⁷,¹⁸ However, advanced technologies using image analysis software are time-consuming and laborious, and are not routinely available to physicians, particularly in primary clinics. This study investigated the associations of visually assessable HRCT parameters with Tr5 using a simple method. We also compared the parameters among the 5 Tr groups.⁸

MATERIALS AND METHODS

Subjects

We performed a cross-sectional, single-center, retrospective study using HRCT images obtained from 59 retrospectively enrolled asthmatics who took part in our previous study.⁸ Briefly, patients met the following criteria: physician diagnosis of asthma and presence of reversible airway obstruction (short-acting BD-induced FEV1 > 12% and 200 mL), airway hyper-reactivity (methacholine provocative concentration causing a 20% fall in FEV1 < 10 mg/mL), or improvement in FEV1 > 20% after 2 weeks of treatment with ICS or systemic corticosteroids. All patients were treated routinely according to the Guidelines for Asthma Treatment issued by the Korean Academy of Asthma Allergy and Clinical Immunology.¹⁹ BD-FEV1 was measured at 3-month intervals over the first year. An HRCT scan was performed after 9–12 months of asthma treatment. Asthma exacerbation was defined as described by the American Thoracic Society/European Respiratory Society Task Force on Asthma.²⁰ All demographic and biodata were obtained from a biobank of Soonchunhyang University Bucheon Hospital, A member of the Korea Biobank Network (KBN4-A06). The protocol was approved by the Ethics Committees of Soonchunhyang Bucheon Hospital (SCHBC-2021-08-31) and Hallym University Sacred Heart Hospital (2021-10-012). Written informed consent for the use of the HRCT images was waived because the study personnel were blinded to personal patient data.

Thin slice computed tomography (CT) scanning and radiological evaluation

A volumetric thin-section CT scan of the chest was performed using a SOMATOM Sensation 16 (16-channel multi-detector CT - Sensation 16; Siemens, Forchheim, Germany). Patients were scanned from the lung bases toward the apices, with 1 mm collimation and a table feed of 6 mm per 0.75-second scanner rotation (8 mm/s) at 120 kV and 140 mA in one breath hold. For the expiratory thin section CT scan, all subjects were instructed to take a deep breath and exhale fully, and then hold their breath. Volumetric axial images of 1 mm thickness, acquired at 10-mm intervals, were reconstructed with a high spatial frequency algorithm at the end of both inspiration and expiration, as previously reported.¹⁶,²¹ All images were displayed using the lung window setting of a Picture Achieving and Communication System (PACS; Starpacs; Infinitt Technology, Phillipsburg, NJ, USA). The 8 HRCT parameters are shown in Supplementary Fig. S1 and can be defined as follows²²: emphysema: a focal area of very low attenuation, usually without a definable wall and surrounded by normal lung parenchyma; bronchiectasis: bronchial dilation compared with the accompanying pulmonary artery, lack of tapering bronchi, or the presence of bronchi within 1 cm of the pleural surface; anthracofibrosis: lymph node enlargement causing diffuse bronchial narrowing²³; BWT: a thickened airway wall larger than the adjacent pulmonary arteries²⁴,²⁵; fibrotic band: a focal area of linear atelectasis with a linear configuration, almost extending to the pleura; mosaic attenuation: regional mosaic attenuation at the end of inspiration; air-trapping: decreased attenuation at the end of exhalation compared with normal lung parenchyma; and centrilobular nodules: small nodules in the center of a normal secondary pulmonary lobule. The images were viewed with 2 window sizes: −450 Hounsfield units (HU) for accurate measurement of BWT, and −700 HU for analysis of other HRCT features including emphysema, bronchiectasis, fibrotic bands, mosaic attenuation, and air-trapping. Anthracofibrosis was evaluated at 50 HU. Two thoracic radiologists blinded to the patients’ clinical history and pulmonary function tests reviewed each HRCT image and reached a consensus. The lung was divided into 6 zones according to 3 planes (upper, middle, and lower horizontal) and 3 vertical distances (between the lung apices and domes of the diaphragm on the right and left lungs). The 8 parameters were scored as present (score 1), or absent (score 0) in each of the 6 lung zones. Emphysema, bronchiectasis, BWT, mosaic attenuation, air-trapping, and centrilobular nodules were scored as 1 when the lesion covered > 30% of the zone, and fibrotic bands as 1 when the lesion extent was > 10%. Anthracofibrosis was scored as 1 when present, regardless of extent. All parameters were summed to yield total scores ranging from 0–6. When the scores differed by > 1 point between the 2 radiologists, the measurement was repeated until they differed by < 1 point.

Statistical analyses

Cluster analysis was performed using a 2-step approach. In the first step, the optimal number of clusters was determined based on hierarchical cluster analysis using silhouette methods, implemented in the NbClust R package using Ward’s method. In the next step, k-means cluster analysis was performed (the principal clustering technique). Kruskal-Wallis and χ² tests were used to compare nonparametric continuous and categorical variables, respectively. For post hoc analysis, the Mann-Whitney U test was used to compare continuous nonparametric variables between 2 Tr groups. Pearson correlation was applied for univariate analysis, with linear regression (backward elimination) used for multivariate analysis. All statistical analyses were performed using SPSS for Windows software (version 24.0; IBM Corp., Armonk, NY, USA).

RESULTS

Baseline characteristics of the subjects

Cluster analysis of the 59 asthmatics revealed a similar distribution of Trs to those reported in our previous study (Supplementary Table S1).⁸ The baseline mean BD-FEV1 (% pred.) values of the Tr4 and Tr5 groups were lower compared to those of the Tr1–3 groups (67.08% ± 7.73%, 48.46% ± 3.97% and 99.61% ± 2.69%, respectively, P < 0.001). In the Tr4 group, BD-FEV1 (% pred.) increased to the normal range by month 3 (93.53% ± 3.39%), while it persistently declined over 1 year in the Tr5 group (61.65% ± 4.06% at 12 months). The baseline characteristics of the subjects are shown in Table 1. The mean age and asthma duration were significantly greater in the Tr5 group than in the other Tr groups (P = 0.007 and 0.017, respectively). The female to male ratio, body mass index, smoking status, and atopy rate were similar among the Tr groups. The Tr4 and Tr5 groups had more exacerbations than the Tr1–3 groups. The Tr4 and Tr5 groups used high-dose ICSs more frequently than the Tr1–3 groups (P = 0.003). The total dose of systemic corticosteroids used to relieve acute exacerbations was significantly higher in the Tr4 and Tr5 than Tr1–3 groups (P = 0.041).

Table 1. Comparison of clinical and laboratory characteristics between Trs.

Variables		Tr1–3 (n = 36)	Tr4 (n = 12)	Tr5 (n = 11)	P value
					Tr1–3 vs. Tr4 vs. Tr5	Tr4 vs. Tr5
Age at enrollment (yr)		47.80 ± 1.34	44.52 ± 2.63	54.90 ± 1.15	0.007	0.004
Male (%)		41.7	33.3	54.5	0.584	0.305
BMI (kg/m2)		23.12 ± 1.05	24.71 ± 0.84	24.71 ± 1.03	0.932	0.782
Smoking status (NS/ES/SM)		26/6/4	6/3/3	5/2/4	0.298	0.822
Smoking amount (pack-year)		5.72 ± 1.91	5.33 ± 2.77	14.09 ± 4.71	0.165	0.312
Atopy (%)		50.00	25.00	45.50	0.318	0.304
Log10 total IgE (U/mL)		2.02 ± 0.12	2.09 ± 0.23	2.33 ± 0.23	0.337	0.325
Asthma duration (yr)		5.83 ± 0.82	7.08 ± 1.65	14.64 ±3.65	0.017	0.064
Age at onset of asthma (yr)		42.07 ± 1.55	36.94 ± 2.66	40.99 ± 3.12	0.216	0.145
Subjects exacerbation rate in the 1st yr (%)		25.00	91.70	72.70	< 0.001	0.231
Exacerbation rate in the 1st 1 yr		0.36 ± 0.12	1.50 ± 0.23	5.09 ± 1.76	< 0.001	0.233
BD response > 12%		5 (13.9)	7 (53.8)	8 (72.7)	< 0.001	0.469
Post-BD-FEV1 change > 200 mL		8 (22.2)	5 (41.7)	2 (18.2)	0.338	0.221
Patients with PC20 < 10 mg/mL		23 (63.9)	11 (91.7)	5 (71.4)	0.186	0.243
Dosage of ICS (µg/day)*		148.78 ± 33.55	297.95 ± 76.36	377.09 ± 80.45	0.037	0.386
	Low dose ICS	26 (72.2)	6 (50.0)	1 (9.1)	0.003	0.096
	Medium dose ICS	7 (19.4)	3 (25.0)	4 (36.4)
	High dose ICS	3 (8.3)	3 (25.0)	6 (54.5)
Dosage of systemic corticosteroid (mg/year)†		95.92 ± 44.11	587.00 ± 260.09	283.18 ± 162.74	0.041	0.197
Blood eosinophils (%)		4.12 ± 0.80	5.38 ± 1.54	3.34 ± 1.31	0.711	0.452
Blood neutrophils (%)		34.93 ± 27.07	40.27 ± 8.13	51.79 ± 8.03	0.218	0.269

Values are presented as mean ± standard deviation or number (%).

Tr, trajectory; BMI, body mass index; NS, non-smoker; ES, ex-smoker; SM, smoker; IgE, immunoglobulin E; BD, bronchodilator; FEV1, forced expiratory volume in 1 second; PC20, provocative concentration causing a 20% fall in forced expiratory volume in 1 second; ICS, inhaled corticosteroid.

^*Dosages were presented as equivalent of fluticasone (µg/day), low dose ICS ≤ 250 µg/day, medium dose 250–500 µg/day, and high dose > 500 µg/day of fluticasone or equivalent.

^†Dosages were presented as equivalent of prednisolone (mg/year).

Comparison of HRCT findings among Trs

The mean emphysema score was 10 times higher in the Tr5 than Tr4 and Tr1–3 groups (3.64 ± 0.68 vs. 0.33 ± 0.19 vs. 0.25 ± 0.11, P < 0.001, Table 2). The difference between the Tr4 and Tr5 groups was highly significant (P < 0.001), while the Tr4 and Tr1–3 groups were similar. The mean BWT score was 2 times higher in the Tr5 than Tr4 groups (3.00 ± 0.52 vs. 1.50 ± 0.45, P = 0.044), and 5 times higher in the Tr5 than Tr1–3 groups (0.64 ± 0.19, P < 0.001). The scores for the other 6 parameters were not significantly different among the Tr groups. When the subjects were grouped as smokers and non-smokers, the emphysema and BWT scores were 2–4 times higher in the Tr5 than Tr4 group smokers (4.00 ± 1.26 vs. 1.00 ± 0.41, P = 0.264, and 3.00 ± 0.63 vs. 0.75 ± 0.48, P = 0.038, respectively, Supplementary Table S2), and in the Tr5 than Tr4 group non-smokers (3.20 ± 0.20 vs. 0.00 ± 0.00, P < 0.001, and 3.00 ± 0.95 vs. 1.88 ± 0.61, P = 0.294, respectively, Supplementary Table S3). The mean fibrotic bands score was higher in the Tr5 than Tr1–3 group non-smokers (1.80 ± 0.86 vs. 0.29 ± 0.10, P = 0.026, Supplementary Table S3).

Table 2. Comparison of scores of the high-resolution computed tomography parameters between Trs.

Variables	Tr1–3 (n = 36)	Tr4 (n = 12)	Tr5 (n = 11)	Overall P value	P value (Tr4 vs. Tr5)
Emphysema	0.25 ± 0.11 (36)	0.33 ± 0.19 (12)	3.64 ± 0.68 (11)	< 0.001	< 0.001
Bronchiectasis	0.31 ± 0.13 (36)	0.08 ± 0.08 (12)	0.09 ± 0.09 (11)	0.642	0.950
Anthracofibrosis	0.00 ± 0.00 (36)	0.17 ± 0.17 (12)	0.00 ± 0.00 (11)	0.141	0.338
Bronchial wall thickening	0.64 ± 0.19 (36)	1.50 ± 0.45 (12)	3.00 ± 0.52 (11)	< 0.001	0.044
Fibrotic band	0.44 ± 0.13 (36)	0.5 ± 0.23 (12)	1.27 ± 0.49 (11)	0.194	0.218
Mosaic attenuation in inspiration	0.00 ± 0.00 (36)	0.17 ± 0.17 (12)	0.09 ± 0.09 (11)	0.203	1.000
Air-trapping in expiration	2.13 ± 0.33 (36)	2.82 ± 0.62 (12)	1.50 ± 0.65 (11)	0.258	0.107
Bronchiolitis	0.64 ± 0.15 (36)	0.67 ± 0.33 (12)	0.45 ± 0.45 (11)	0.292	0.232

Numbers of parenthesis indicate the number of patients to be scored for the analysis.

Tr, trajectory.

Correlations of the scores for HRCT parameters with BD-FEV1 during follow-up

BD-FEV1 (% pred.) during follow-up was inversely correlated with the emphysema (Pearson’s r = −0.579, P = 1.57 × 10⁻⁶), and BWT (r = −0.506, P = 4.39 × 10⁻⁵) scores in univariate analysis (Figure). In multivariate analysis, the emphysema and BWT scores remained significantly correlated with BD-FEV1 (% pred.) (β = −6.893 ± 1.681, P < 0.001 and β = −4.535 ± 1.558, P = 0.006, respectively) (Table 3). The linear regression equation for BD-FEV1 was as follows: BD-FEV1 (% pred.) = −7.455 × (Scores of Emphysema) + 99.324, and BD-FEV1 (% pred.) = −6.936 × BWT + 101.326. When the 2 parameters were combined, BD-FEV1 was estimated as follows: BD-FEV1 (% pred.) = −6.016 × (Score of Emphysema) − 4.830 × (Score of BWT) + 102.253 (R = 0.659, P = 6.38 × 10⁻⁷).

Figure. Correlation of post-BD-FEV1 (% pred.) with emphysema (A) and bronchial wall thickness (B) scores. The linear regression equation for BD-FEV1 (% pred.) was as follows: BD-FEV1 (% pred.) = −7.455 × (Score of Emphysema) + 99.324, and BD-FEV1 (% pred.) = −6.936 × (Score of BWT) + 101.326.

BD, bronchodilator; FEV1, forced expiratory volume in 1 second; BWT, bronchial wall thickening.

Table 3. Correlation between the 8 parameters of high-resolution computed tomography and bronchodilator-forced expiratory volume in 1 second (% pred.) at the follow up of 12 months.

Variables	Univariate correlation		Multivariate analysis
	R	P value	β	Standard error of β	P value
Emphysema	−0.579	< 0.001	−6.893	1.681	< 0.001
Bronchiectasis	0.005	0.972	4.692	3.590	0.198
Anthracofibrosis	0.086	0.517	-	-	-
Bronchial wall thickening	−0.506	< 0.001	−4.535	1.558	0.006
Fibrotic band	−0.170	0.199	−0.240	2.442	0.922
Mosaic attenuation	−0.161	0.222	−4.553	7.815	0.563
Air-trapping	0.041	0.770	−1.072	1.321	0.421
Bronchiolitis	0.056	0.674	1.611	2.229	0.473

DISCUSSION

In this study, we demonstrated that emphysema and BWT in HRCT images were associated with persistent airflow limitation in asthmatics, despite almost 1 year of treatment, using a simple and semi-quantitative method. Our data agree with several cross-sectional studies that quantitatively assessed asthmatics; BWT and emphysema are more common in patients with severe asthma compared to mild asthma.¹²,¹⁵,¹⁷,¹⁸,²⁶,²⁷ Gupta et al.¹⁵ reported prevalence rates of BWT and emphysema in severe asthma patients of 62% and 8%, respectively. BWT, assessed using imaging software, was associated with asthma severity and disease duration. Likewise, in our study, the Tr5 patients, who exhibited a persistently low BD-FEV1 (% pred.; approximately 60%) had 2 times higher BWT scores compared to patients with a normal BD-FEV1 (% pred.; approximately 90%). Airway remodeling explains the persistent airflow obstruction in some asthmatics caused by the pathological changes such as goblet cell hyperplasia, subepithelial collagen deposition, increased reticular basement membrane thickness, airway smooth muscle mass, and angiogenesis of the airways.²⁸,³⁰ These findings have also been reported in mild asthmatics.³¹ In our study also, the mean BWT score was 0.64 for the Tr1–3 patients (Table 2), who were mild asthma having a normal BD-FEV1 (% pred.) and 10 of the 36 Tr1–3 patients had BWT scores ≥ 1 (data not shown).

Airway remodeling begins in pre-school-age children as young as 1 year, and persists throughout adulthood.³²,³³ Childhood-onset asthma typically appears prior to the age of 12 years, and 40% of adult asthmatics report symptoms after 40 years of age.³⁴,³⁵ In this study, the Tr5 group had the longest mean asthma duration (14 years), but the onset time was not different among the Tr groups; thus, remodeling does not appear to depend on the age of onset. Smoking is closely associated with deterioration of lung function in asthmatics. The rate of decline in lung function is accelerated in smokers with asthma compared to nonsmokers, and a proportion of smokers with asthma develop persistent airflow obstruction.³⁶,³⁷ Chronic smoking induces distinct inflammatory and structural changes in the lungs. The luminal area of the large airways on HRCT is reduced in smokers with severe asthma, particularly in those with a history of chronic mucus hypersecretion, possibly due to smoke-induced mucus hypersecretions and airway remodeling.³⁸,³⁹ In our study, a difference in BWT scores was seen between the Tr4 and Tr5 group of smokers, indicating that a thickened airway wall may be an irreversible consequence of persistent airway obstruction, particularly in smokers. However, the Severe Asthma Research Program (SARP) cohort, which included only never smokers or less than 10-pack year ex-smokers, demonstrated that the mean WT% was significantly higher in asthmatics with severe lung function decline than those with normal or improved lung function during 3-year follow-up.⁴⁰ Hartley et al.⁴¹ also showed that the mean WA% in nonsmoker asthmatics negatively correlated with FEV1, indicating that BWT is a representative finding reflecting airway remodeling in severe asthma. In the current study, subgroup analyses with nonsmokers showed that BWT scores tended to be higher in the Tr5 than in the Tr4 groups without statistical significance, which might be due to a small sample size of these two study groups in this study. Thus, further studies using a large asthma cohort, including smokers and nonsmokers, are warranted to replicate this result.

In this study, the most notable finding was that the emphysema scores were 10 times higher in the Tr5 compared to Tr4 group. Previous studies reported emphysematous changes in 15%–39% of asthmatics, with the most prevalent being centrilobular emphysematous changes.¹⁷,⁴² Emphysema is closely related to smoking history, although it is also present in nonsmoking asthmatics.⁴³ Recently, Shimizu et al. ²⁹ reported that asthmatics with fixed airway obstruction had parenchymal destruction in low-attenuation areas, regardless of smoking status, which was associated with an accelerated decline in FEV1. These data indicate that emphysema, presenting as parenchymal destruction on HRCT, can occur in severe asthmatic patients with reduced lung function. In this study, the emphysema scores were 4 times higher in the Tr5 than Tr4 groups, even when only non-smokers were compared, indicating the irreversible nature of the persistent airway obstruction seen in this group. However, this does not accord with other studies.⁴¹,⁴⁴ The discrepancy between our results and those of other studies may arise from the methods used, i.e., semi-qualitative versus quantitative analysis. However, the higher emphysema scores of the non-smokers in our Tr5 group than in the Tr4 group could be explained as follows: during aging, the human lung undergoes a remarkable transformation, characterized by both structural and functional alterations.⁴⁵ Age-dependent decrements in FEV1 proceed linearly from 25–30 years of age, and then accelerate with increasing age.⁴⁶ Lung parenchymal structural changes affecting elastic recoil are postulated to underlie peripheral airway narrowing, with a reduced airway surface to volume ratio being observed in the elderly.⁴⁷ Elderly patients with no known underlying lung disease also exhibit alveolar dilation and ductal ectasia, without emphysema or fibrosis.⁴⁸ In our study, the Tr5 group was the oldest. Thus, the high rate of emphysema seen in the non-smoking Tr5 group patients may be attributable to its high proportion of older-subjects.

In this study, the bronchiectasis, anthracofibrosis, mosaic attenuation, air-trapping, and centrilobular nodule scores were not significantly different between the Tr4 and Tr5 groups. This is not in line with previous studies, in which these parameters were significantly increased in severe asthmatic patients.⁴⁹,⁵⁰ The discrepancies between our study and previous ones may arise from the small numbers of subjects and differences in the methods used. We used a simpler classification system for the parameters of interest (present vs. absent) compared to the quantitative lesions measures applied in other studies.⁴¹,⁵¹ For measuring HRCT parameters other than BWT and emphysema, our simple method may not be adequate.

Our study had several limitations. First, 2 pulmonary radiologists manually assessed the 8 parameters of interest on each HRCT image, rather than using automated computer software; this may have affected the accuracy. In addition, the BWT scores were not adjusted for body surface area, and the regional distribution of air-volume changes could not be determined, in contrast to previous quantitative studies.²⁶,⁴¹ However, our semi-quantitative method could be more suitable for use in clinical practice. Secondly, the follow-up duration (for assessment of lung function) was < 1 year, which is relatively short. However, recent data from SARP 3,⁵² which included a 3-year follow-up, indicated that the wall area and air-trapping percentages of baseline CT scans were associated with a more severe subsequent decline of lung function, similar to our results. Thirdly, we only analyzed follow-up HRCT images, and could not assess longitudinal changes due to a lack of HRCT scans at enrollment. Finally, the number of patients was relatively small; therefore, our results require validation in a larger cohort.

In conclusion, using an easy to perform semi-quantitative method, we demonstrated that severe asthma characterized by persistently disturbed lung function was associated with both parenchymal and airway destruction, as indicated by increased emphysema and BWT scores. In addition, our linear regression model predicted the degree of airflow limitation based on BD-FEV1. Thus, our semi-quantitative method for measuring BWT and emphysema may be useful to distinguish phenotypes of asthma, particularly among patients with persistent airflow limitation. However, other parameters including bronchiectasis, anthracofibrosis, mosaic attenuation, air-trapping, and centrilobular nodules cannot be adequately analyzed using our method. Thus, an advanced method using deep learning technology, which provides time and labor savings, will be used in future to evaluate the airway and parenchymal changes seen in asthma.

SUPPLEMENTARY MATERIALS

Supplementary Table S1

Longitudinal changes of post-BD-FEV1 (% pred.) in 5 Trs

Supplementary Table S2

Comparison of scores for the high-resolution computed tomography findings in smokers

Supplementary Table S3

Comparison of scores for the high-resolution computed tomography findings in non-smokers

Supplementary Fig. S1

Representative high-resolution computed tomography images: emphysema (A), bronchiectasis (B), anthracofibrosis (C), bronchial wall thickening (D), fibrotic band (E), mosaic attenuation in inspiration (F), air-trapping in expiration (G), and centrilobular nodules (H).