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Keywords:

  • airway luminal area;
  • airway wall;
  • computed tomography;
  • multiplanar reconstruction;
  • small airway

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background and objective:  COPD and bronchial asthma are chronic airway diseases with a different pathogenesis. Comparisons of differences in airway calibre by bronchial generation between these diseases and their importance to pulmonary function have not been fully studied. We investigated airway calibre and wall thickness in relation to pulmonary function in patients with asthma, COPD, asthma plus emphysema and normal subjects using CT.

Methods:  Sixty-three asthmatic patients, 46 COPD, 23 patients with asthma plus emphysema and 61 control subjects were studied cross-sectionally. We used a software with curved multiplanar reconstruction to measure airway dimensions from 3rd- to 6th-generation bronchi of the right lower posterior bronchus.

Results:  Patients with COPD had increased wall thickness, but the airway was not narrow from the 3rd-(subsegmental) to 6th-generation bronchi. Mean bronchial inner diameter (Di) of 3rd- to 6th-generation bronchi in patients with asthma or asthma plus emphysema was smaller than that of COPD patients and normal subjects. Airway luminal area (Ai) of 5th-generation bronchi most closely correlated with pulmonary function in patients with stable asthma. Although Di was similar in patients with asthma and asthma plus emphysema, the Ai of 6th-generation bronchi correlated significantly with pulmonary function in patients with asthma plus emphysema.

Conclusions:  Airway calibre in asthma may be smaller than in COPD. Airflow limitations correlated more closely with peripheral Ai in patients with asthma plus emphysema than in patients with asthma alone.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

COPD is a disease characterized by airflow limitation that is not fully reversible and consists of small airway disease and emphysema.1 Thin-section high-resolution computed tomography (HRCT) has been used to quantify the extent of emphysema in COPD.2,3 However, FEV1 does not correlate well with the severity of emphysema as evaluated by low attenuation area on HRCT.4 Physiological and pathological studies suggest that small airway disease contributes more significantly to airflow limitation in COPD.5,6 Hasegawa et al. found that distal airway dimension, not large airway dimension, was related to airflow limitation in COPD.7 Matsuoka et al. further demonstrated that airway luminal area (Ai) measured at expiratory CT was more closely related to expiratory airflow limitation than was luminal area measured at inspiratory CT.8

Asthma is also a chronic inflammatory airway disease characterized by reversible airflow obstruction and airway hyperresponsiveness.9 This inflammation is present throughout the airways, from the central to the peripheral airways.10,11 There is strong evidence to indicate that small airways significantly contribute to total airway resistance.5,12 It has been reported that wall thickness of the single central bronchus in the right upper and lower lobe can estimate FEV1 in patients with bronchial asthma.13 These observations of COPD and asthma suggest different implications of Ai on pulmonary function between these diseases. Theoretically, thin-section HRCT can measure airways as small as approximately 1–2 mm in inner diameter. Hasegawa et al. developed a new software for measuring airway dimensions using curved multiplanar reconstruction by which they could obtain longitudinal images and accurately analyze short-axis images of small airways with inner diameters as small as 2 mm located anywhere in the lung.7 With the progress in CT technology, we are now able to measure small airways with inner diameters of less than 2 mm and airway dimensions up to the 7th generation of bronchi using similar software. With this software, we can obtain accurate cross-sectional images and longitudinal airway images such that we can recognize bronchial generations accurately. In this study, we directly compared bronchial inner diameter (Di) in the right lower lobe of patients with asthma, COPD and asthma with emphysema, and normal subjects, and additionally compared Ai and bronchial wall thickness. We then examined the relations between Ai and pulmonary function in these diseases.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

CT data acquisition and reconstruction

A 256-slice CT scanner (Brilliance iCT; Philips Healthcare, Cleveland, OH, USA) was used. CT scans were acquired with the following parameters: 120 kVp, 200 effective mAs, 128 × 0.625-mm detector collimation and helical pitch of 0.915. All scans were obtained at suspended end-inspiratory volume. All CT row datasets were reconstructed to use both soft tissue and bone algorithms with a section thickness of 1 mm and a reconstruction interval of 0.5 mm. The length of the 1-pixel side was 0.38–0.49 mm. Reconstructed data were transferred to the workstation, and airway segmentation and measurements of Ai were obtained with newly developed software (Philips Healthcare). In transverse reconstructed images with a window width of 1300 Hounsfield units (HU) and window level of −600 HU on the workstation monitor, we selected the target airways and a point in the airway lumen at the level of the sub-subsegmental bronchus that was as distal as possible. From this point, the airway tree was identified by use of a seeded region-growing algorithm, and we obtained the selected bronchial pathway. We could then obtain short-axis images that were exactly perpendicular to the long axis at any site. From the centroid point of the lumen, rays fanning out over 360 degrees were examined to determine inner airway walls along the rays by using the full width at half maximum principle.14,15 After this process, we could obtain mean values for the airway luminal Di and airway wall thickness (T) at intervals of 3.0 mm along the long axis of the bronchus. Assuming that the airway lumen is a true circle and airway wall thickness is constant throughout the wall, the Ai and the outer area of the bronchus (Ao) were calculated as Ai = (Di/2)2 × π and Ao = ((Di + T)/2)2 × π. The wall area per cent was defined as WA% = (Ao − Ai)/Ao × 100.

Validation of measurements

We performed validation analysis by using five phantoms to test the software. The phantoms were made of acrylic resin, and their inner and outer diameters and Ts were measured by optical micrometre caliper. Phantom A had a Di of 0.8 mm and T of 1.1 mm. Phantom B had a Di of 1.5 mm and T of 1.0 mm. Phantom C had a Di of 1.8 mm and T of 1.0 mm. Phantom D had a Di of 3.0 mm and T of 1.0 mm. Phantom E had a Di of 4.9 mm and T of 1.0 mm.

Subjects

The Institutional Review Board of Saitama Cardiovascular and Respiratory Center approved this retrospective, cross-sectional study that waived the need for informed consent. CT scans of the subjects were undertaken during disease follow up or for screening of minor changes seen on chest X-ray.

Patients with asthma

Adult subjects with asthma had a history of mild to severe persistent asthma by National Heart, Lung, and Blood Institute Asthma Guidelines criteria.9 Inclusion criteria for patients with asthma were that their symptoms had been controlled or occurred less than two times per week without asthma exacerbation during the previous 1 month, and they were classified as having mild to severe persistent asthma based on treatments required. Patients with smoking history were excluded.

Patients with COPD

Patients with COPD were diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease guidelines.1 Subjects who had an allergic history, an episodic wheeze, high serum IgE or sputum eosinophils were excluded from the study. We also excluded patients whose symptoms were not clear for COPD or asthma.

Patients with asthma plus emphysema

Asthma patients who satisfied the above asthma guidelines with a definite history of asthma, and who had high serum IgE and airway reversibility but also a considerable history of smoking (>40 pack years) and emphysema on HRCT were analyzed separately.

Normal subjects

CT data were obtained from non-smoking normal subjects who underwent chest CT for an annual health check or for closer examination of minor chest abnormalities.

Data analysis of airway measurements

To measure airway dimensions, we selected the posterior basal bronchus of the right lower lobe. In this study, a subsegmental bronchus was defined as a 3rd-generation bronchus according to the guidelines of the Japanese Cancer Society.16 We selected only one bronchus for evaluation in each generation. Analysis was limited to the 3rd through the 6th generations because the number of detected bronchi was low after the 6th generation. Mean values of airway lumen diameter in each bronchial generation were calculated from at least three points to obtain a complete outline of the bronchial wall.

Pulmonary function tests

Pulmonary function tests (PFTs) were performed within 2 weeks of obtaining the thin-section CT scans. PFTs were performed according to the guidelines of the American Thoracic Society17 and measured with a CHESTAC8800 (Chest Inc., Tokyo, Japan).Values for each PFT except that of FEV1/FVC were expressed as percentages of predicted values.

Statistical analysis

Data are expressed as mean ±standard deviation of the mean (SD). Differences between gender ratios were compared with the chi-square test. Statistical analysis between groups was first done with the Kruskal–Wallis test followed by the Scheffé test for comparisons between groups. The relations between Ai in each bronchial generation and the PFT results were evaluated with Spearman rank tests. A value of P < 0.05 was considered to be significant. StatView 5.0 (Abacus Concepts Inc., Berkeley, CA, USA) was used for the analyses.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Validation of measurements

The results for Di, T and Ai measured in the five silicon tube phantoms as assessed with the software are shown in Table 1. Measurements of Di obtained with the software slightly overestimated diameters when compared with the diameters measured by optical micrometre calibre. The mean coefficient of variation for five measurements of Ai from 49 different points of each tube were 4.6% for Tube B, 2.6% for Tube C, 1.3% for Tube D and 1.9% for Tube E. The mean coefficient of variation for five measurements of WA% from 49 different points of each tube were 1.3% for Tube B, 1.0% for Tube C, 1.0% for Tube D and 1.2% for Tube E. These data indicate that the measurement of airway dimensions by the software is very accurate and reproducible for airways with a Di ≥ 1.5 mm.

Table 1.  Variability of the data in the measurements of the phantoms
 Actual valueValue measured (mean ± SD)CV(%) (mean ± SD)
  1. Ai, airway luminal area; CV (%), coefficient of variation; WA, airway wall area; WA (%), WA/(WA + Ai) × 100.

Tube AAi (mm2)0.5NANA
(0.8 mm)%WA92.92%NANA
Tube BAi (mm2)1.771.95 ± 0.204.60%
(1.5 mm)%WA81.63%83.35 ± 1.751.30%
Tube CAi (mm2)2.543.20 ± 0.252.60%
(1.8 mm)%WA77.56%75.78 ± 1.481.00%
Tube DAi (mm2)6.837.72 ± 0.631.30%
(3.0 mm)%WA64.48%64.61 ± 1.581.00%
Tube EAi (mm2)18.8619.64 ± 1.301.90%
(4.9 mm)%WA49.57%49.78 ± 1.581.20%

Clinical study

Patient characteristics are reported in Table 2. There was no significant difference in male/female ratio in asthma and control groups, but most of the patients with COPD or asthma plus emphysema were males. Spirometry was measured in all of the patients, but DLCO was measured only in part of the patients. Airflow limitations in the COPD and asthma plus emphysema groups were significantly more severe than those in the asthma group, and both COPD and asthma plus emphysema groups showed decreased DLCO.

Table 2.  Clinical characteristics of patients included in studies
 AsthmaCOPDAsthma + emphysemaControl
  1. Data are expressed as mean ± SD.

  2. DLco were measured in 25 patients with asthma, 45 patients with COPD and 20 patients with asthma plus emphysema.

  3. MEF25, maximum expiratory flow rate at 25% FVC; MEF50, maximum expiratory flow rate at 50% FVC; MEF75, maximum expiratory flow rate at 75% FVC; ND, not determined.

Subjects (n)63462361
Gender(male/female)30 / 3344 / 222 / 130 / 31
Age (years)60.1 ± 12.369.3 ± 7.467.3 ± 6.762.3 ± 12.7
Smoking (pack yrs)069.3 ± 33.668.6 ± 36.70
FVC (% predicted)82.1 ± 19.484.2 ± 19.869.9 ± 17.497.7 ± 13.2
FEV1 (% predicted)81.3 ± 26.365.5 ± 26.549.9 ± 23.5111.8 ± 18.7
FEV1/FVC64.7 ± 13.646.3 ± 13.943.9 ± 12.580.4 ± 10.3
MEF75 (% predicted)49.6 ± 28.326.8 ± 21.017.3 ± 14.2102.2 ± 19.0
MEF50 (% predicted)33.5 ± 23.217.6 ± 15.111.9 ± 9.976.7 ± 20.1
MEF25 (% predicted)24.6 ± 17.619.2 ± 14.212.3 ± 6.768.1 ± 22.1
DLco (% predicted)96.8 ± 26.863.5 ± 21.866.2 ± 16.5ND

The results for Di are shown in Figure 1. The respective mean and 2SD lower range of Di at 3rd-generation bronchi in normal subjects were 4.9 mm and 4.0 mm, and were 3.9 mm and 3.2 mm at 4th-generation bronchi, 3.2 mm and 2.6 mm at 5th-generation bronchi, and 2.6 mm and 2.0 mm at 6th-generation bronchi.

image

Figure 1. Airway inner diameter (Di) of the 3rd (subsegmental) to the 6th generation of the right lower posterior bronchus in patients with COPD, asthma and asthma plus emphysema, and in normal control subjects. Horizontal bars within the boxes indicate the median values, boxes represent the 75th and 25th percentiles, and the short horizontal bars represent the 90th and 10th percentiles.

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The respective mean and 2SD lower range of Di at 3rd-generation bronchi in COPD patients were 4.7 mm and 3.7 mm, and were 3.9 mm and 3.0 mm at 4th-generation bronchi. There were no significant differences in Di measurements between control subjects and COPD patients in 3rd- to 6th-generation bronchi. However, the Di's of 3rd- to 5th-generation bronchi of patients with asthma and patients with asthma plus emphysema were significantly smaller than those of the control subjects and COPD patients. Representative CT images of bronchial diameters in COPD and asthma are shown in Figure 2.

image

Figure 2. Longitudinal and short-axis images of the right lower posterior bronchus from patients with COPD and bronchial asthma. Panels a and c show longitudinal and short-axis images, respectively, of 4th-generation bronchi of COPD (measured inner diameters were 4.2 mm). Panels b and d show longitudinal and short-axis images, respectively, of 4th-generation bronchi of asthma (measured inner diameters were 2.3 mm). Note the relative diameters of the bronchi in comparison to their accompanying arteries (circular solid white areas).

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The results of measurements of WA% are shown in Figure 3. The WA% values in 3rd- to 6th-generation bronchi in patients with COPD, asthma, and asthma plus emphysema were significantly larger than those in the control subjects. There were no significant differences in WA% between the asthma and asthma plus emphysema patients, but the values were significantly larger than those of the control subjects and COPD patients.

image

Figure 3. Wall area percent (WA%) of the 3rd (subsegmental) to the 6th generation of the right lower posterior bronchus in patients with COPD, asthma, and asthma plus emphysema, and in normal control subjects. Horizontal bars within the boxes indicate the median values, boxes represent the 75th and 25th percentiles, and the short horizontal bars represent the 90th and 10th percentiles.

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The relations between Ai and pulmonary function are shown in Table 3. In patients with asthma, pulmonary function as described by %FEV1, %MEF75 (maximum expiratory flow rate at 75% FVC), %MEF50 (maximum expiratory flow rate at 50% FVC) and %MEF25 (maximum expiratory flow rate at 25% FVC) correlated most closely with Ai at the 5th generation of bronchi, although the correlation of Ai with %FEV1 was weak (r = 0.433). In patients with asthma plus emphysema, Ai at the 6th-generation bronchi correlated significantly with %FEV1, %MEF75 and %MEF50. Ai at 3rd generation of bronchi weakly correlated with pulmonary functions in this group. We observed no correlations between Ai and pulmonary function in patients with COPD or in the control subjects.

Table 3.  Relation between airway luminal area and pulmonary function tests
 %FEV1%MEF75%MEF50%MEF25
r valueP valuer valueP valuer valueP valuer valueP value
  1. %MEF25, % predicted maximum expiratory flow rate at 25% FVC; %MEF50, % predicted maximum expiratory flow rate at 50% FVC; %MEF75, % predicted maximum expiratory flow rate at 75% FVC.

Asthma
3rd generation0.3060.01690.4500.00030.4560.00020.3980.0015
4th generation0.3500.05800.4700.00010.4910.00010.4370.0004
5th generation0.4330.00050.526<0.00010.565<0.00010.521<0.0001
6th generation0.2910.02370.3620.00420.3550.00510.2780.0309
Asthma + emphysema
3rd generation0.4010.05730.4750.00210.4440.03270.4280.0408
4th generation0.0920.68110.1790.41930.0990.65760.0500.8217
5th generation0.2280.29940.2950.17540.2180.32130.1220.5849
6th generation0.6840.00020.6260.00100.5100.01190.3570.0949

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In this study, we demonstrated that knowledge of the Di of 3rd-(subsegmental) or 4th-generation bronchi was helpful to distinguish asthma or asthma plus emphysema from COPD or normal controls. We also showed that the Ai of 5th-generation bronchi was most closely related to pulmonary function in patients with stable asthma, whereas the Ai of 6th-generation bronchi correlated with pulmonary function in patients with asthma plus emphysema.

Airway diameter in COPD and asthma has received less attention than Ai or wall thickness. Even in normal subjects, widely used geometry of conducting airways has been analyzed by inflating the lungs with plastic or polyester resin at a fixed lung volume.18–20 To our knowledge, the measurements of airway diameter at each bronchial generation in real life has not been possible until the development of CT software as used in this study or in other recent reports.7,8 King et al. reported a Di of <1 mm in asthmatics and normal subjects, but they did not report Di itself at defined bronchial generation.21 In supine normal subjects, the pulmonary artery is equal in diameter to the accompanying bronchus observed by CT.22–24 As shown in Figure 2, the typical diameter of a 4th-generation bronchus in COPD can be recognized as being the same diameter as or larger than the accompanying artery. However, the diameter of an asthma bronchus is often smaller than that of the accompanying artery. The results of the present study imply that not all asthma bronchi are narrow, but an inner diameter of <4 mm at 3rd-generation bronchi or < 3 mm at 4th-generation bronchi suggest the presence of asthma or asthma plus emphysema. We previously studied the aetiology of 516 patients with chronic airflow limitation that was not fully reversible and reported a significant overlap in airway reversibility among COPD, asthma and other airway diseases.25 The CT evaluation of airway calibre in addition to low attenuation area might be helpful to distinguish between COPD and asthma. We chose to measure the Di of the right lower posterior bronchus (rtB10) because our data could be helpful for diagnosis by conventional CT because the cross-section of the rtB10 can be easily recognized without the need for specific software.

By using the software reported herein in combination with multi-detector CT, we could measure bronchi down to 1 mm in diameter, and the phantom validation study demonstrated that short-axis images of bronchi with an inner diameter as small as 1.5 mm were accurately measured. The detection limit of this system enabled us to study the small airways (<2 mm in diameter) in COPD and asthma. Our data clearly showed that peripheral airways were narrow and thick even in patients with controlled asthma. In accordance with this observation, these patients showed decreased %MEF50 and %MEF25 values. In patients with COPD, there was no significant difference in Di compared with normal subjects; however, the increased WA% of COPD patients also suggests airway involvement at these bronchial levels.

Another focus of this study was the relation between pulmonary function and CT findings. It is not clear why the Ai of 5th-generation bronchi correlated closely with peripheral airway markers such as %MEF50 and %MEF25, whereas the Ai of 6th-generation bronchi correlated less closely with these parameters in patients with asthma. In contrast, the Ai of 6th-generation bronchi correlated closely with %FEV1 and %MEF75 in patients with asthma plus emphysema. There was no significant difference between these groups in Di and WA% throughout the observed airways. We assumed that the loss of lung parenchyma in patients with asthma plus emphysema would result in a reduction in elastic recoil, although no physiological measurement of elastic recoil was made in this study. A certain point of an airway would partially collapse or inflate at forced expiration according to the dynamic balance of elastic recoil pressure of the lung, pleural pressure, and airway pressure at a certain point.26,27 Airways in patients with asthma plus emphysema would collapse more easily at forced expiration than in patients with asthma alone. In addition, the collapse may be more significant if upstream (peripheral) airways are narrow. Our data suggest that peripheral airway narrowing may result in considerable downstream (central) airway collapse at forced expiration in patients with asthma plus emphysema. However, future studies from other approaches will be required to further understand the relations between airway dimension and lung function in asthma patients with or without emphysema.

We observed increased wall thickness but no relation between Ai and pulmonary function in COPD patients. Matsuoka et al. previously reported that 3rd- to 5th-generation bronchi collapsed significantly at expiration in COPD.8 It suggests a significant loss of elastic recoil in this group. It is possible that peripheral airway obstruction may influence the collapse of 3rd- to 5th-generation bronchi at expiration in COPD, but we did not observe airway obstruction up to 6th-generation bronchi in COPD. The important role of small airway lesions has been well recognized in the airflow limitations of COPD.5,6,28,29 We have to study more peripheral parts of the airway in COPD, and through the development of CT technology, it may be possible in near future.

There are several limitations to the present study. First, we assessed only one bronchus, that of rtB10. Variations in airway dimensions may exist even in normal subjects,30 but previous reports showed that only one bronchus of the right upper lobe statistically correlated with pulmonary function.13,31 In a previous report, relations between Ai and lung functions were similar in three different lobes.8 Nevertheless, it would be important to reveal the variations and heterogeneities of airway obstruction in patients with asthma and COPD in future studies. Second, the range of confidence intervals of Di depends on the accurate clinical diagnosis of COPD and asthma. We previously reported that only 54.3% of patients whose FEV1/FVC was < 70% after inhalation of a bronchodilator were diagnosed as having COPD.22 In the present study, we selected patients strictly diagnosed with COPD as described previously.22 In addition, we excluded those patients whose symptoms were not clear for COPD or asthma. According to the current guidelines for asthma and COPD,1,9 it is sometimes difficult to define patients who have both COPD and asthma. Therefore, we defined asthma plus emphysema as the group of patients with a typical asthma history and airway eosinophilia as well as definite emphysema on HRCT. However, the scale of this study is limited, and future multicentre studies are needed to establish definite criteria for airway calibre.

In conclusion, the geometry of conductive airways in patients with asthma was significantly different from those of patients with COPD or normal subjects. Patients with COPD had increased wall thickness, but the airway was not narrow from the 3rd- to 6th-generation bronchi. In patients with asthma, however, the airway was narrow and thick from the 3rd- to the 6th-generation bronchi, even in patients with fairly well-controlled asthma. Peripheral Ai correlated more closely with pulmonary function in patients with asthma plus emphysema than in patients with asthma alone.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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