Airway Distensibility by HRCT in Asthmatics and COPD with Comparable Airway Obstruction

Abstract

Introduction: Decreased airway distensibility (AD) in response to deep inspirations, as assessed by HRCT, has been associated with the severity of asthma and COPD. Aims: The current study was designed to compare the magnitude of AD by HRCT in individuals with asthma and COPD with comparable degrees of bronchial obstruction, and to explore factors that may influence it. Results: We enrolled a total of 12 asthmatics (M/F:7/5) and 8 COPD (7/1) with comparable degree of bronchial obstruction (FEV₁% predicted mean±SEM: 69.1 ± 5.2% and 61.2 ± 5.0%, respectively; p = 0.31). Each subject underwent chest HRCT at FRC and at TLC. A total of 701 airways (range 20 to 38 airway per subject; 2.0 to 23.1 mm in diameter) were analyzed. AD did not differ between asthmatics and COPD (mean ± SEM: 14 ± 3.5% and 17 ± 4.3%, respectively; p = 0.58). In asthmatics, AD was significantly associated with FEV₁% predicted (r² = 0.45, p = 0.018). We found a significant correlation between the change in lung volume and the change in AD by HRCT (r² = 0.64, p = 0.002). In COPD, we found significant correlations between AD and the RV% predicted (r² = 0.51, p = 0.046) and the RV/TLC (r² = 0.68, p = 0.01). Conclusions: AD was primarily affected by the dynamic ability to change lung volumes in asthmatics, and by static lung volumes in COPD.

Keywords: :

• lung volumes
• deep inspirations
• imaging

Introduction

In asthma and COPD, the functional alterations can be defined not only by the degree of bronchial obstruction but also by the magnitude of the dilatory response of the airways to deep inspirations (DIs). DIs exert their effects on airways through the radial traction that is applied to the airway wall by virtue of the interdependence between intraparenchymal airways and the surrounding parenchyma. Radial traction is sustained by a network of alveolar attachments to the airway walls: thus, any factors altering the airways and the parenchyma can cause a reduction in the distending forces leading to a reduced ability of DIs to bronchodilate (1). Increased thickness of the airway wall, such as that observed in the more severe stages of asthma (2, 3), or the loss of alveolar attachments, such as that documented in the emphysematous lungs (4, 5), can impair the ability to distend airways. Both in asthmatics (6, 7) and in COPD (8, 9), we found that the severity of the disease, as assessed by lung function impairment, was associated with the decreasing bronchodilatory ability of DI.

DIs exert their effects on airways through the radial traction that is applied to the airway wall by virtue of the interdependence between intraparenchymal airways and the surrounding parenchyma. Radial traction is sustained by a network of alveolar attachments to the airway walls: thus, any factors altering the airways and the parenchyma can cause a reduction in the distending forces leading to a reduced ability of DIs to bronchodilate. Increased thickness of the airway wall, such as that observed in the more severe stages of asthma, or the loss of alveolar attachments, such as that documented in the emphysematous lungs, can impair the ability to distend airways. Scichilone et al. (4), and Corsico et al. (5), demonstrated that the number of destroyed alveolar attachments is correlated with blunted DI-induced bronchodilation in COPD subjects who had undergone surgical resection of lung parenchyma. However, the need of obtaining lung tissue severly limits the possibility of implementing research activities aimed at understanding the mechanisms involved in the pathogenesis of bronchial obstruction.

High resolution computed tomography (HRCT) has been used to obtain non-invasive assessment of airway measurements and parenchymal density in individuals with obstructive pulmonary diseases (10–13). We hypothesized that the mechanism for decreased bronchodilatory ability of DIs would vary by the etiology of the disease. The current study was designed to determine which factors affected the magnitude of DI-induced AD as measured by HRCT in asthmatic and COPD subjects with comparable degree of bronchial obstruction.

Methods

Subjects

We enrolled unselected consecutive individuals who fulfilled the diagnostic criteria for either asthma (14) or COPD (15), respectively. Patients visiting the Outpatient Clinic for Respiratory Diseases of the University of Palermo, Italy, were asked to participate in the study. All the enrolled subjects were clinically stable at the time of the study. Asthmatics had partially or totally controlled disease, as assessed by the Asthma Control Test (ACT) at the time of the recruitment (ACT > 20 in all subjects). Before each study visit, all subjects were asked to abstain from inhaled, short-acting β-agonists or anticholinergic agents for at least 12 hours, or long-acting bronchodilators for at least 24 hours. The protocol was approved by the Ethics Committee of the University of Palermo, Palermo, Italy, and written informed consents were obtained.

The study was performed on 2 days. The first visit included clinical and functional assessments. On a separate occasion, within 7 days, the lung imaging was carried out. By design, all subjects were in stable clinical conditions at both study days.

Study design

Clinical and functional assessments

Clinical and demographic data included age, sex, duration of disease, frequency of exacerbations in the previous year, and current treatment. Functional assessment was made of static and dynamic lung volumes using the helium dilution technique and a computerized water-sealed spirometer (Biomedin; Padua, Italy). Measurements were made in accordance to the European Thoracic Society standardisation of lung volume measurements (16).

Imaging assessment

Each subject underwent HRCT evaluation, which was performed by spiral computed tomography (multidetector 64 channels, Philips Medical System, Cleveland, OH), with a setting of 120 kVp, 200 mAs, a 0.9-mm slice thickness, a rotation time 0.5 s, and a reconstruction interval of 0.45 mm, pitch 0.923, during a single breath and moved caudally. Images were reconstructed at a window level of −600 Hounsfield units (HU) and a window width of 1600 HU. Two sets of scans were obtained: the first one was acquired at the end of the expiratory phase of the tidal volume (presumably functional residual capacity, FRC) and the second one at maximal lung inspiration (presumably total lung capacity, TLC). Subjects were trained to perform these maneuvers immediately prior to the scanning procedure. Any portion of the scan with motion artifact from breathing was discarded. We also made sure that the time course of the inspiration and the expiration phases were equal in all subjects, since it is known that this can affect the lung volume history (17).

The change in airway diameter measured at TLC and at FRC (airway distensibility, AD) represented the main outcome of the study. Airway wall fraction (AWF, airway wall thickness as a fraction of the airway diameter) and lung density were measured to evaluate which radiological abnormalities potentially affected the main outcome. The occurrence of diffuse fibrosis of the lung and/or other abnormalities (parenchymal infiltrates, cystic lesions) potentially affecting the density of the lung represented an exclusion criterion. The validated Pulmonary Workstation 2 software package (VIDA Diagnostics, Inc, Iowa City, IA) was used (18–20).

Airway measurements

AD was measured by applying the following formula to each individual airway:

In addition, we arbitrarily divided the airways into three groups by size: small (< 4 mm in airway diameter), medium (4–8 mm in airway diameter) and large (>8 mm in airway diameter), and AD was expressed for each airway size group.

Parenchymal measurements

measured total lung volume and parenchymal density on the HRCT scans as an estimate of parenchymal damage. Lung total volume was calculated automatically and expressed in cm³. Parenchymal density was expressed by lung attenuation parameters, such as mean lung density at FRC (Mean HU_exp) and at TLC (Mean HU_insp), the percent of the lung with a low attenuation area at TLC below -950 HU (LAA_-950) as an estimate of the degree of emphysema, and the percent of the lung with low attenuation area at FRC below −856 (RA_–856) as an estimate of the degree of air trapping.

Data Analysis

Data analysis was performed using JMP 9.0.1 software (SAS Institute Inc., North Carolina). Wilcoxon sign rank tests were performed for paired comparisons, simple linear regressions, and step-wise linear regression where appropriate. Results are expressed as mean ± SEM. Significance level was set at p ≤ 0.05.

Results

A total of 12 asthmatics (M/F: 7/5) and 8 COPD (M/F: 7/1) were studied. Demographic and clinical lung function characteristics of the study subjects are presented in Table 1. By design, the magnitude of airway obstruction, as assessed by FEV₁% predicted and FEV₁/FVC%, was not different between the asthmatic and COPD subjects. FVC% predicted was significantly lower in COPD (p = 0.04). As expected, the diffusing capacity for CO was significantly lower in COPD group than in asthmatic group (p = 0.03). HRCT measured lung volumes and lung attenuations did not differ between groups (Table 2).

Table 1.  Demographic and lung function characteristics of the study subjects

Condition	Sex	Age	Smoking	Medications	Duration of disease (years)	Exacerbation*	FEV1% red	FVC% Pred	FEV1/FVC	FEF 25–75% Pred	MEF 25% Pred	MEF 50% Pred	MEF 75% Pred	RV% pred	TLC% pred	DLCO% pred
A1	m	47	n	1, 2, 5	25	2	56	101	44.5	16	13	17	27	156	113	118
A2	m	52	e	1, 2	6	2	60	72	67.8	30	21	32	44	155	98	106
A3	m	56	n	1	5	4	89	88	80.8	84	80	93	55	62	75	79
A4	m	58	n	1, 2, 5	30	3	66	84	62.7	23	14	27	46	118	93	119
A5	m	60	n	1, 2	7	1	49	71	54.6	23	18	24	26	114	84	78
A6	f	60	e	1, 2, 5	35	4	101	115	73.4	52	33	62	115	107	105	100
A7	f	37	n	1, 2, 5	22	1	51	76	58.1	22	17	22	39	99	139	93
A8	m	30	n	1, 2	17	2	70	95	62.4	31	21	37	62	153	106	98
A9	m	66	n	1	5	1	55	90	47.8	20	25	22	60	112	128	80
A10	f	64	n	1, 2	6	0	67	88	63.6	23	20	24	34	111	105	85
A11	f	59	e	1, 2	40	1	65	95	57.5	24	28	23	37	117	121	90
A12	f	71	n	1, 2	7	1	100	131	61.9	30	30	33	60	98	97	97
Asthma (mean ± SEM)		55 ± 3.4			17.1 ± 3.7		69.1 ± 5.2	92.2 ± 5.0	61.2 ± 2.9	31.5 ± 5.4	26.7 ± 5.2	34.7 ± 6.3	50.4 ± 6.9	116.8 ± 7.8	105.3± 5.2	95.2 ± 4.0
C1	m	64	e	1	8	1	84	100	66.2	41	35	52	57	136	102	80
C2	m	74	e	1, 3	10	2	57	65	67.6	40	26	66	66	131	89	87
C3	m	76	e	1, 3	6	1	60	63	71.5	36	26	43	73	121	87	79
C4	m	69	e	1	2	1	81	91	69.2	43	32	53	84	101	97	90
C5	m	63	e	1, 3	6	1	59	81	57.8	29	29	30	30	111	101	76
C6	m	74	e	1, 3	4	2	52	65	61.3	26	21	24	38	95	73	85
C7	m	61	e	1, 3, 4	3	1	43	80	42.5	11	16	10	14	116	91	86
C8	f	58	e	1, 3	10	2	54	56	81.7	46	56	43	34	119	96	78
COPD (mean ± SEM)		67± 2.4			6.1 ± 1.1		61.2 ± 5.0	75.1 ± 5.4	64.7 ± 4.0	34 ± 4.1	30.1 ± 4.2	40.1 ± 6.3	49.5 ± 8.5	116.2± 4.9	92± 3.3	82.6 ± 1.8

A = Asthma, C = COPD. m = male, f = female. Smoking: e = ex-smoker, n = non-smoker.

Medications: 1 = Inhaled corticosteroids + long acting beta-agonists, 2 = antileukotriene, 3 = tiotropium, 4 = theophylline, 5 = omalizumab.

*Number of exacerbations in the previous year.

Table 2.  HRCT measured lung volumes and lung attenuations in asthmatics and COPD subjects

	Asthma	COPD	p-value
Lung volumes at FRC	3588 ± 354.6 cm^3	3968 ± 434.3	0.82
Lung volumes at TLC	4896 ± 376.1 cm^3	5408 ± 460.7 cm^3	0.54
Mean HUinsp	−818.3 ± 11.4 HU	−832.2 ± 14 HU	0.88
Mean HUexp	−758 ± 15.6 HU	−764 ± 19.1 HU	0.82
LAA–950	10.6 ± 2.4%	15.5 ± 2.9%	0.35
LAA–856	29.3 ± 4.5%	33.2 ± 5.6%	0.82

A total of 701 airways (range 20 to 38 airway per subject; 2.0 to 23.1 mm in diameter) were analyzed. We did not find a significant difference neither in the mean AWF between groups (at TLC: p = 0.44; at FRC: p = 0.40), nor when airways were examined by size (p = 0.25, p = 0.40, p = 0.35 for small, medium and large airways, respectively).

The AD by airway size was similar between the two groups (Table 3). In addition, the HRCT-change in lung volume with inspiration from FRC to TLC did not differ between the asthmatic (40 ± 8%) and COPD (42 ± 10%) groups (p = 0.70). In the asthmatic group, AD significantly correlated with FEV₁% predicted (r² = 0.45, p = 0.018) (Figure 1), but not with FVC% predicted (r² = 0.23, p = 0.11), or FEV₁/FVC (r² = 0.24, p = 0.10). In addition, AD did not correlate with TLC% predicted (r² = 0.02, p = 0.63), RV% predicted (r² = 0.22, p = 0.12), or RV/TLC (r² = 0.07, p = 0.40). Finally, no correlation was found between AD and DLCO% predicted (r² = 0.02, p = 0.67). We also found a significant correlation between the change in lung volume as measured by HRCT (to the 1/3 power) and the change in AD (r² = 0.64, p = 0.002, Figure 2).

Figure 1.  Correlation between baseline lung function expressed as FEV₁% predicted and the degree of airways distensibility by deep inspirations in the asthmatic group (r² = 0.45, p = 0.018).

Figure 2.  Correlation between the change in lung volume as measured by HRCT (to the 1/3 power) and the change in airways distensibility by deep inspirations in the asthmatic group (r² = 0.64, p = 0.002).

Table 3.  Airway distensibility by size in asthmatics and COPD subjects

	Asthma	COPD	p-value
Small airways	22 ± 4.1%	29 ± 5.0%	0.27
Medium airways	14 ± 3.6%	14 ± 4.4%	0.94
Large airways	5 ± 2.2%	8 ± 2.7%	0.40

In the COPD group, no relationships were found between AD and FEV₁% predicted (r² = 0.01, p = 0.81), FVC% predicted (r² = 0.05, p = 0.59), FEV₁/FVC (r² = 0.01, p = 0.88), TLC% predicted (r² = 0.01, p = 0.93), or DLCO% predicted (r² = 0.01, p = 0.79). However, significant correlations were found with RV% predicted (r² = 0.51, p = 0.046) and RV/TLC (r² = 0.68, p = 0.01, Figure 3). We found no relationship between the change in lung volume (to the 1/3 power) and the change in AD (r² = 0.41, p = 0.08). Finally, AD was inversely correlated with the mean airway diameter at FRC (r² = 0.58, p = 0.03).

Figure 3.  Correlation between baseline lung function expressed as RV/TLC% predicted and the degree of airways distensibility by deep inspirations in the COPD group (r² = 0.68, p = 0.01).

Next, we performed stepwise multiple linear regression analyses, and made two separate models for the asthmatic and the COPD subjects. For the asthmatic subjects, the variables that entered in the model were the RV% predicted (p = 0.03), the percent change in lung volume (p = 0.0009), and the mean airway diameter at TLC (p = 0.004). This model accounted for 88% of the variance in AD (r² = 0.88, p = 0.0004). For the COPD subjects, the variables that entered in the model were the TLC% predicted (p = 0.02), and the RV/TLC (p = 0.008), the greater the RV/TLC the greater the AD. Also, RV% predicted entered the model and after correcting for the TLC and RV/TLC was in the anticipated negative direction, the greater the RV%, the lower was the AD. However, it did not reach statistical significance (p = 0.057). This model accounted for 94% of the variance in AD (r = 0.94, p = 0.0056).

Discussion

The present study was designed with the objective of evaluating the magnitude of AD by HRCT in individuals with asthma and COPD with similar degrees of airway obstruction. We also explored the factors that may influence AD in our study populations. Our primary finding was that the mean AD either overall or by airway size did not differ between the asthmatic and COPD subjects. However, the major determinants of AD were different for the two groups. In the asthmatics, the dynamic ability to change lung volume was the main factor that affected AD, yet in the subjects with COPD, the static lung volumes positively influenced the degree of AD, although the latter association appears to be counterintuitive.

Our finding of a lack of differences in AD between two different chronic respiratory diseases, asthma and COPD, is attractive and deserves some speculation. Studies incorporating the HRCT methodology to assess changes in airway diameter were commonly performed in asthmatics and in COPD separately (1, 6, 8). In our study, using a multiple-regression model, we found that the AD in the asthmatic group was inversely correlated with the RV% predicted and was directly dependent on chances in lung volumes and the maximum size of the airways at TLC, which is consistent with our initial hypothesis. Whether by simple linear regression or by stepwise multiple regression, the change in lung volume was the most significant factor with regards to AD in the asthmatics. We infer from these results that for asthmatic individuals, AD was predominantly dependent on the change in lung volume. Indeed, one of the factors that influence the magnitude of the distending forces is the extent to which the lungs can inflate. In the presence of lung hyperinflation, a common state in moderate-to-severe airway obstruction in asthma, further lung inflation by DI may be impaired.

Contrary to the logical concept that increased thickness of the airway wall, such as that observed in the more severe stages of asthma, should induce greater stiffness of airways, which in turn would oppose airway distension, we were not able to demonstrate an association between airway wall thickness and AD. This observation is in line with the findings of Pyrgos et al. (6). Thus, while airway walls have been shown to be thicker (1), this increased thickness does not appear to impede AD. We infer from these findings and previous work (6), that the remodeling processes in asthma that increase the airway wall thickness do not appear to change the basic force-tension dynamics in vivo, and do not appear to make airways more resistant to imposed stretch by DI.

In the COPD subjects, by simple linear regression, RV/TLC alone accounted for 82% of the variance in AD (r = 0.82, p = 0.01), and remained a significant independent predictor of AD in the stepwise regression model. However, it remains curious that this was a positive correlation, i.e. the greater the RV/TLC, the greater was the AD. This at first appears to be counterintuitive. While the correlation for air trapping as measured by the RA_-856 was in the “right” direction (negative: the greater the air trapping, the less was the distensibility) the correlation was not significant (r = −0.45, p = 0.27). There are several possibilities for this counterintuitive finding. Brown et al. using a forced oscillation technique found that approximately 80% of total AD occurred between 75% TLC and TLC (21). Therefore, as RV/TLC increases, RV increases greater than TLC increases, and the increase in TLC leads to an increase in lung volume, and thus AD will be on the steeper part of the distensibility versus lung volume portion of the curve (21).

Another possibility may be mechanical. With increased RV/TLC in the subjects with COPD, the increased lung volumes may allow increased radial traction from the reduced numbers of parenchymal attachments that distend the airways with further inspiration. It is also important to note that the range of RV/TLC values for the COPD subjects were limited (range: 42 to 61; Figure 3). How AD would respond in individuals with COPD with more extreme values of RV/TLC will need to be examined. Another possible mechanism for the increased distensibility with increased RV/TLC may be that the airway smooth muscle has adapted to a new L₀ from being in a chronically distended state (22). The airways could be on a new passive length-tension curve due to the chronic hyperinflation in COPD.

In addition, in contrast to the asthmatic subjects, where dynamic factors were associated with AD, in the COPD subjects, static factors were associated with the AD, specifically the TLC% predicted and the RV/TLC ratio entered the stepwise model and were statistically correlated with the AD in the multiple regression model. While the relationship between the change in lung volume and AD was in the right direction it did not reach statistical significance in the simple linear regression model (r = 0.64, p = 0.08) and did not enter the stepwise regression model.

The study has some limitations. The relatively small number of subjects could potentially account for the lack of differences in terms of AD between groups. We envision this as a pilot study to determine which factors can affect the magnitude of AD in asthmatic and COPD subjects with comparable degrees of bronchial obstruction. In addition, the AD has been used as primary outcome in previous studies with similar study group size (6, 8). Although the emphysema score was approximately 50% greater in the COPD compared to the asthma subjects, the emphysema scores, the air trapping scores, and the airway wall thicknesses were not statistically different between asthmatic and COPD subjects. There are some possible explanations for these findings. The most plausible explanation that can be advocated is that our COPD subjects were randomly selected for not showing extensive emphysematous abnormalities of the lungs.

This could account for the lack of differences in the emphysema score, and likely in the amount of air trapping. The possibility also exists that that air trapping may not be distinguishable from emphysema-associated changes at low lung volume. Similarly, the condition of hyperinflation in the asthmatic subjects may not be distinguishable from emphysema-associated changes in the COPD subjects at high lung volume on HRCT. These features could limit the ability of HRCT to discriminate between the two study groups.

In summary, our findings demonstrate that the extent of AD is similar in asthmatic and COPD individuals with a similar level of airway obstruction. While hyperinflation as measured by increased RV limits AD in asthma, it appears to favor distensibility in COPD. In asthmatic individuals, the reduction in AD was related to the degree of obstruction as measured by the FEV₁, the greater the obstruction the greater was the loss of AD. Although the reduction in AD in individuals with COPD may be more acute, with the loss of parenchymal attachments reaching a critical level which leads to loss of AD. Thus, we infer from our results that the etiology of the reduced airway distensibility was disease specific. Therefore, treatment of the loss of bronchodilation due to reduced AD will require different approaches in asthmatic and COPD individuals.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.