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1 University of British Columbia, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, 2 Dept of Radiology and Thoracic Imaging Group, Vancouver Hospital, 3 Dept of Radiology, UBC Hospital, 4 Centre for Health Evaluation and Outcome Sciences, St. Paul's Hospital, Vancouver, Canada. 5 Woolcock Institute of Medical Research, University of Sydney 2006, and 6 Cooperative Research Centre for Asthma, Sydney, Australia
CORRESPONDENCE: G.G. King, Woolcock Institute of Medical Research, University of Sydney 2006, Sydney, Australia. Fax: 61 299066391. E-mail: ggk@woolcock.org.au
Keywords: Airway narrowing, asthma, heterogeneity, quantitative high resolution computed tomography
Received: April 30, 2003
Accepted April 16, 2004
This work was supported, in part, by an operating grant from the Canadian Institutes of Health Research. G.G. King was supported by a MRC/CLA postdoctoral fellowship #9611J9N-1003-46453, an Astra/MRC/PMAC Canada Fellowship and AstraZeneca ALF grant-in-Aid.
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Abstract |
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The current authors defined heterogeneity as variability in narrowing greater than the repeatability of measurement. Airways of <2 mm diameter were compared with larger airways from baseline and postmethacholine HRCT of the right lower lung in 13 normals (seven had repeat baseline scans) and seven asthmatics. The coefficient of repeatability was calculated from repeat scans (RepAi) and was compared with heterogeneity of narrowing measured by the variability in narrowing from pre versus postmethacholine scans (Var
Ai).
Forced expiratory volume in one second decreased 27±6% and 24±8% in normals and asthmatics, respectively. Airways >2 mm narrowed more heterogeneously in asthmatics (VarAi=±0.85 mm) compared with normals (VarAi=±0.67 mm), with both being greater than the measure of repeatability (RepAi=±0.16 mm). Small airway narrowing was not heterogeneous in asthmatics (VarAi=±0.59 mm) or normals (VarAi=±0.53 mm) compared with repeatability (RepAi=0.51 mm).
It is possible to study heterogeneity of airway narrowing in small and large airways using high resolution computed tomography. Airway narrowing is heterogeneous in the large airways of asthmatics and normals, being greater in asthmatics.
Airway hyperresponsiveness (AHR), characterised by increased sensitivity and maximal narrowing in response to nonspecific stimuli, is an important feature of asthma and other airway diseases. Many factors could contribute to AHR, however, it has been suggested that heterogeneity of airway narrowing, in and of itself, could be an important contributor 1, 2.
Results from studies of inhaled gas radioisotopes 3 have shown the development of heterogenous airway closure and increased ventilation/perfusion mismatch after bronchoconsticting stimuli, especially in asthmatic subjects 4–6. These findings are consistent with narrowing or closure of the large airways (
2 mm diameter) and are concordant with the results of high-resolution computed tomography (HRCT) studies of human airway narrowing 7–9. Although narrowing has been measured in large airways by direct imaging, the evidence for heterogeneous narrowing has been indirect (i.e. heterogeneous ventilation). Therefore, the level at which heterogeneity occurs is unknown. In contrast, HRCT offers the potential for direct invivo visualisation of human airways and a comparison ofnarrowing between airways of different size. Results of a HRCT study of canine airways suggest that airways narrow heterogeneously after the administration of airway smooth muscle (ASM) agonists either by aerosol or intravenously 10.
Heterogeneity of airway narrowing can be measured by the sd of the change in airway lumen area (Ai), as was done in modelling studies 1, 2. However, when measuring heterogeneity of narrowing, the results can only be interpreted in relation to the inherent variability in the measurements of Ai. If measurements of Ai are poorly repeatable (i.e. sd of repeated measurements is large), then any heterogeneity of narrowing that is small relative to this repeatability will be obscured by the inaccuracies of measurement. The corollary is that even if airway narrowing is homogeneous, narrowing could appear to be heterogeneous if measurements are poorly repeatable. It is only when the sd of narrowing is compared with the measurement repeatability that heterogeneity can be meaningfully interpreted.
In the present study, the authors examined the hypothesis that airways narrow heterogeneously after methacholine inhalation in normal and asthmatic subjects and that heterogeneity is greater in asthmatics. Ai was measured from HRCT scans using a previously validated algorithm in normal and asthmatic subjects. To determine the repeatability of measurement, RepAi were performed without inducing bronchoconstriction. To measure heterogeneity of narrowing, the variability of the change in Ai between pre and postmethacholine scans was measured.
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Methods |
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Subjects
Altogether, 10 nonasthmatic and four asthmatic male subjects were recruited from staff of the University of British Columbia i-CAPTURE Center (table 1 and 2
, subjects 1–10, 14–17), and three normal and three asthmatic male subjects were recruited from staff and patients of the Woolcock Institute of Medical Research Australia (table 1 and 2, subjects 11–13, 18–20). Spirometry and methacholine challenges were initially performed in the laboratory with the subjects supine. The baseline forced expiratory volume in one second, forced vital capacity and inspiratory capacity (IC) were measured and expressed as per cent predicted based on the equations of Crapo et al. 11. Normal subjects had no chronic respiratory symptoms, disease diagnosis or long-term medication use. Asthma was diagnosed according to the American Thoracic Society guidelines. All subjects were current non or exsmokers of <10 pack-yrs.
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0.55, the subjects' requested stopping or when the maximal concentration had been administered. Full spirometry was then performed and the IC was measured from the first manoeuvre. The Rpartial was used as an indication of airway narrowing and to guard against excessive airway narrowing for safety reasons during the challenge. However, FEV1 was used as the primary measure of airway narrowing. In Canada, asthmatic subjects underwent methacholine challenges starting at a concentration of 0.25 mg·mL–1 followed by doubling concentrations using a Hudson Bennett Twin Jet Nebuliser (Hudson Bennett, Temecula, CA, USA) and 2 min of tidal breathing via a face mask according to the protocol of Juniper et al. 14. In Australia, asthmatic subjects underwent methacholine challenges using the rapid method 15 using DeVilbiss Number 45 hand-held nebulisers (DeVilbiss, Heston, UK) in cumulative doubling doses from 0.03–8 µmol. The challenge was otherwise identical to that described above for the normal subjects.
HRCT scanning
HRCT was performed using a CT9800 Whole Body Scanner (General Electric (GE), Milwaukee, WI, Canada) in Canada and a CTI Whole Body Scanner (GE) in Sydney. Both of these single-matrix scanners were used in helical mode with 1-mm collimation, a pitch of 1, a 40-cm field of view (FOV), 120 kV peak and 200 mA. At baseline, 2 cm axial length of lung caudad to the inferior pulmonary ligament was scanned during a single breath-hold, which yielded 20 contiguous images of 1-mm thickness (i.e. no gap between scans). A repeat baseline scan was obtained 
5 min later in subjects 2, 5, 9–13 (table 1
) during another breath-hold manoeuvre. The final dose of methacholine that had been given in the laboratory was readministered to subjects 1–10 and 14–20 after which a 1-cm axial distance of lung, that was within the baseline HRCT field, was rescanned.
The known relationship between airway calibre and lung volume led the present study to standardise this for both the baseline and postmethacholine HRCT. The current authors didthis by controlling lung volume during the baseline scan using a water-seal spirometer in the following manner. With the CT scanner tube already rotating, subjects inhaled to total lung capacity from the water-seal spirometer, then exhaled the predetermined IC slowly and were prompted to breath-hold when the predetermined lung volume had been reached, at which time scanning commenced. The predetermined IC was that measured at the completion of the methacholine challenge on day 1. For postmethacholine scans, subjects were instructed to breath-hold at end expiration (i.e. at functional residual capacity) and to signal this by waving their hand, at which time scanning commenced. All scans were, therefore, performed during breath-hold and the degree of hyperinflation (i.e. IC) was assumed to be similar for methacholine challenges done at the time of the HRCT to that after methacholine in the lung function laboratory. The comparison of the ICs after the methacholine challenges in the laboratory and CT suite (tables 1 and 2) showed this to be a satisfactory method.
The CT image data were reconstructed using a high-spatial frequency algorithm (GE "bone algorithm") using a 20 cm reconstruction FOV and a 512x512 matrix (pixel size 0.39x0.39 mm=0.15 mm2) focused on the right lung. The same airways were compared in pre and postmethacholine scans by matching the branching patterns of the pulmonary vessels 7. All airways that could be successfully matched and in which lumen measurements could be made (fig. 1) using the authors' semi-automated computer algorithm (see below), were used in the analysis.
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300 g·L–1 and corrected for both airway size and angle of orientation in relation to the central axis of the scanner, calculated from the x, y and z displacements of the lumen centroids of slices above and below the slice being analysed. In effect, measurements were derived from cross-sectioned, rather than oblique, images.
For analyses, all Ai measurements were square root transformed (
Ai) because Ai is a squared function of airway diameter. Mean airway narrowing for each subject was measured as the slope of the regression between baseline Ai versus postmethacholine Ai, for which there was a linear relationship in all subjects. Mean narrowing was also calculated as the mean per cent change in Ai, for airways grouped by their baseline internal diameter (<1 mm, 1–2 mm, etc.), calculated from the Ai. Pre and postmethacholine Ai's were compared using ANOVA and Duncan's post hoc test.
Data analyses
The repeatability of Ai measurements (RepAi) were calculated from the repeat Ai measurements made from the two baseline scans, by the methods of Bland and Altman 17, where:
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Ai between airways, in response to methacholine inhalation (VarAi), were calculated from the Bland and Altman plots of the differences in pre and post methacholine Ai versus the baseline Ai 17. Hence:
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Ai measurements of each airway versus baseline Ai and by the Kendall rank correlation tau statistic (=0.11, p=0.09) 17. Finally, it was assumed that the errors in measurement were the same for both RepAi and postmethacholine scans. This was likely since the quality of images (absence of motion artefact) and matching of CT slices were comparable for both the RepAi and the postmethacholine scans. |
Results |
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shows the individual data for age and lung function in the normal subjects. The mean FEV1% predicted was 85±2% in normal subjects and <80% in two subjects. This low mean value is probably due to the subjects' supine position causing a small decrease in lung volume 18, which was supported by the FEV1/FVC ratio being normal in all but one subject. The mean baseline Rpartial was 0.75±0.02. The FEV1 and FVC decreased by 27±6% and 12±4%, respectively at the end of the methacholine challenge. Table 2 shows the individual data for age and lung function in the asthmatic subjects. The mean FEV1% pred was 69±6. The FEV1 and FVC decreased by 24±8% and 16±7%, respectively.
Table 3 shows the degree of airway narrowing in all subjects as measured by the slope of the linear regression between baseline Ai versus postmethacholine Ai. There was no difference in mean slopes between asthmatic and normal subjects (0.91±0.05 and 0.80±0.04, respectively, p>0.05). There were no significant relationships between the slope of baseline Ai versus postmethacholine Ai, and changes in FEV1, IC or Rpartial of subjects. The decrease in FEV1 after methacholine was related to the degree of hyperinflation measured by the per cent change in IC in normals and asthmatics combined (R2=0.29, p=0.04). There was no relationship between the mean percentage change in Ai and change in FEV1 in asthmatics and normals combined.
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shows the percentage changes in Ai between pre and postmethacholine scans, by initial airway size, in 144 normal airways. Airways were categorised as <1 mm (n=7), 1–2 mm (n=68), 2–3 mm (n=47), 3–4 mm (n=17) and >4 mm (n=5). The changes in 99 asthmatic airways are similarly shown in figure 2b. Airways were also categorised as <1 mm (n=18), 1–2 mm (n=33), 2–3 mm (n=22), 3–4 mm (n=14) and >4 mm (n=12). There was no significant change in mean Ai of airways that had an initial internal diameter <1 mm at baseline (p>0.05) in both asthmatic and normal subjects but significant narrowing occurred in larger airways in both asthmatic and normal subjects (p<0.05). In normals, narrowing in airways <1 mm in diameter was less than narrowing in the other groups. In asthmatic subjects, mean airway narrowing in airways 1–2 mm in diameter was greater than the mean narrowing in airways <1 mm (p=0.02) and >4 mm (p=0.03) diameter.
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is a Bland and Altman plot of repeatability of Ai measurements and the scatter of data points shows their repeatability (a total of 110 airways from seven subjects). The repeatability coefficient (RepAi) was ±0.48 mm. Figure 3b is a Bland and Altman plot of the differences in baseline Ai and postmethacholine Ai, versus baseline Ai in normal subjects (a total of 144 airways from 10 subjects) from which VarAi was 0.66 mm. Similarly, figure 3c shows the degree of heterogeneity of airway narrowing within asthmatic subjects (a total of 99 airways from seven subjects) from which VarAi was 0.74 mm. The RepAi and VarAi for individuals are shown in Table 3.
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shows the repeatability of Ai measurements, when expressed as a percentage of baseline Ai. The poor repeatability of Ai measurements in the smaller airways, due to limitations in resolution, indicates that it is more difficult to measure airway narrowing as a percentage change in baseline Ai, in these airways. Furthermore, this limitation could also have led to "data censoring" and underestimation of heterogeneity (data censoring could occur if airways that narrowed a lot could not be identified postbronchoconstriction leading to overrepresentation of airways that narrowed less). Consequently, the present study also compared variability by airway size; initial airway diameter <2 mm and 2 mm. Narrowing of small airways (<2 mm diameter) was not heterogeneous since repeatability (RepAi=0.51 mm) was similar to variability of airway narrowing in normals (VarAi=0.53 mm) and asthmatics (VarAi=0.59 mm). In airways 2 mm diameter, airway narrowing was heterogeneous compared with repeatability (RepAi=0.16 mm) in both normals (VarAi=0.67 mm, p<0.01) and asthmatics (VarAi=0.85 mm) with heterogeneity of airway narrowing being greater in asthmatics than normals. The number of airways measured to determine repeatability was greatest in subject nine who also had the worst repeatability. Excluding data on subject nine did not alter any of the findings of heterogeneity.
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Discussion |
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Lung volume had to be controlled because of the known relationship between lung volume and airway calibre 19 by using a spirometer and asking the nonbronchoconstricted subjects to exhale a standardised volume from full lung inflation; this volume was equal to the postbronchoconstriction IC after the final inhalation of methacoholine on day 1. Variability in measurements of Ai in repeated HRCT scans could have arisen from small changes in the position of the subjects between scans, from small errors in the matching of airways, from the inherent limitations in the resolution of HRCT for detecting the inner edge of the airways and from differences in the lung volume at which the scans were acquired due to differences in lung volume at full inflation. In addition, spontaneous variability of regional ASM tone could also have contributed to the variability. Airway calibre has been found to vary by as much as two-fold over several weeks in an HRCT study of dogs 20, while spontaneous variability in calibre of normal airways has also been suggested to occur based on the presence of intrabreath variation in respiratory system impedance 21.
The finding of greater narrowing of larger airways after methacholine inhalation in the present study is similar to the finding of Okazawa et al. 7 who measured airway narrowing in six normal and six asthmatic subjects using HRCT. Smaller airways may indeed narrow less, however, another possibility is data censoring due to the limitations of resolution of HRCT. Lumen measurements from baseline scans were excluded from the analysis if Ai was unmeasurable in postmethacholine scans, even though many were probably either closed or narrowed to below the limits of HRCT detection. This would result in lesser degrees of apparent airway narrowing in small airways. The limits of HRCT resolution are clearly evident in the data in figure 4, which shows repeatability calculated as a percentage of baseline airway diameter. The repeatability coefficient for airways of <2 mm diameter was 85% compared with 37% for larger airways. It was, therefore, unlikely that the current study would be able to measure airway narrowing in airways of 1 mm diameter since their Ai was <0.79 mm2, which represents only 5 pixels.
Another limitation on the measurements of heterogeneity was the volume of lung that it was possible to scan in the present study. The number of airways examined and the number of scans per individual, were limited due to restrictions in radiation exposure. The current work scanned the lower lung zones because this region has more airways which run in an axial direction and analysed only airways in the right lung because of cardiac motion artefact in the left lung. In addition, scanning the lung bases maximised the number of airways that could be measured in each subject, which is an important consideration when measuring variation in narrowing within subjects. There is no theoretical reason or published data to suggest heterogeneity should be limited to a single lung or region. Both the number of airways that were sampled and the repeatability of Ai measurements determined the power with which it was possible to detect heterogeneous airway narrowing in the present study. Since only a mean of 14±2 airways per subject were studied out of thousands of airways, this limited sampling meant that the current study was unable to adequately describe the true degree of heterogeneity.
The presented results are in contrast with the report of Brown et al. 10, who found substantial heterogeneity of airway narrowing in dogs using HRCT. Possible explanations include species differences and/or differences in scanning technique. Maximal shortening of canine ASM 22 is approximately twice that of human ASM 23, which may permit a greater range of narrowing. Greater shortening of canine ASM has been confirmed in vivo by Brown and Mitzner 24 who reported that large airways could narrow by 90% after methacholine challenge. Differences in technique include scanning of a larger lung volume in animals since radiation exposure is not a concern, and minimisation of motion artefacts by ventilatory control of the paralysed and mechanically ventilated animals. These differences would tend to reduce measurement variability and reveal real differences in the degree of airway narrowing between airways. Despite the potential advantages of an animal preparation, some of the heterogeneity reported by Brown et al. 10 could have been due to measurement variability, since they did not report the repeatability of their measurements.
Interestingly, no significant correlation was found between the mean decrease in airway lumen diameter, as measured by HRCT, and physiological measurements of airway narrowing; FEV1 and Rpartial. The partial FEV1/FVC ratio was used in the present study as a measure of airway narrowing, although it was not, in fact, the primary measure of airway narrowing, for which the FEV1 was used. The partial FEV1/FVC ratio has been described by Skloot et al. 13 for modified methacholine challenge tests in which deep inspirations were prohibited. It has also been used by Brown et al. 8 once again to study the effects of prohibition of deep inspiration during modified challenges in five normal subjects using HRCT. They found a relationship between Rpartial and the change in airway lumen area on HRCT. The disparity between the current findings and those of Brown et al. 8 may have been due to differences in methods of volume standardisation, differences in the magnitude of airway narrowing or differences in airway sizes that were imaged in the current study. Since the measurement of FEV1 requires a deep inspiration, and since it is well documented that deep inspiration can largely reverse airway narrowing in normal subjects 13, 25, 26, it is not surprising that this measurement did not correlate with HRCT measurements. However, the measurement of Rpartial was made before a deep inspiration and one might have expected it to correlate with the airway dimensions. Alternatively, the small number of airways, and subjects that were sampled in the present work and the interplay of multiple parameters in determining maximal expiratory flow and the ratio of partial FEV1 to partial FVC are probably responsible for the lack of association.
The importance of the presented data is that they are direct measurements of the variability of airway narrowing, whereas all previous data of heterogeneity of airway narrowing in humans were indirect. As such, the magnitude and sites at which heterogeneity occur could only have been inferred. Mathematical modelling of the effects of serial and parallel heterogeneity have allowed interpretations on global measurements of lung function, such as multiple breath nitrogen washout 27 and frequency dependence of resistance 28. The results of such studies suggest that human airway narrowing is heterogeneous and greater in asthmatics. The current findings of more heterogeneous narrowing in asthmatic airways compared with normal airways also supports findings from the modelling studies of airway resistance 28.
In summary, the present study has documented the repeatability of in vivo measurements of airway lumen area, as measured by high-resolution computed tomography, in normal subjects and found that the constraints of high-resolution computed tomography resolution limited the ability to measure airway narrowing and heterogeneity of airway narrowing in very small airways of <1 mm internal diameter. Airway narrowing was found to be heterogeneous in large airways in normal and asthmatic subjects, with the degree of heterogeneity being greater in asthmatics. These data also help to set limits on the size of airways that can be reasonably evaluated and the number of airways and subjects that need to be studied in future high-resolution computed tomography experiments of airway narrowing and heterogeneity of airway narrowing. The implications of the current findings are that, to more robustly study the clinical and physiological significance of heterogeneity using airway imaging, methods of measuring airway dimensions must become more reproducible. If and when objective measurements of airway narrowing, using high-resolution computed tomography, come into routine use in clinical practice, it will be necessary to define the repeatability of measurements so that the statistical significance of changes associated with disease or treatment can be determined. Such improvements are likely to arise from multi-matrix scanning technology, which allow faster scanning and less motion artefact, higher resolution detectors and improved three-dimensional segmentation methods that are validated using biological lung standards.
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Acknowledgements |
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Footnotes |
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, b) heterogeneity of narrowing of normal airways shown in Bland and Altman plots of: the difference between 
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