The computed tomographic scan: a new tool to monitor asthma treatment?

Abstract

Patients with asthma present with wheeze, cough, chest tightness, and shortness of breath. These symptoms result from excessive airway lumenal narrowing in response to shortening of the circumferential smooth muscle (1Moreno R.H Hogg J.C Pare P.D Mechanics of airway narrowing.Am Rev Respir Dis. 1986; 133: 1171-1180PubMed Google Scholar). Mechanisms of excessive airway narrowing include increased shortening of smooth muscle, due to an imbalance between the ability of the muscle to develop force and the loads opposing shortening and an exaggeration of the effects of muscle shortening on the airway lumen area due to increased thickness of the airway wall between the airway smooth muscle and the lumen (1Moreno R.H Hogg J.C Pare P.D Mechanics of airway narrowing.Am Rev Respir Dis. 1986; 133: 1171-1180PubMed Google Scholar). The increased thickness of the airway wall observed in severe and mild cases of asthma (2Carroll N Elliot J Morton A James A The structure of large and small airways in nonfatal and fatal asthma.Am Rev Respir Dis. 1993; 147: 405-410Crossref PubMed Scopus (649) Google Scholar) could account for excessive airway narrowing in the presence of normal (or increased) smooth muscle shortening (1Moreno R.H Hogg J.C Pare P.D Mechanics of airway narrowing.Am Rev Respir Dis. 1986; 133: 1171-1180PubMed Google Scholar). Increased thickness of the airway wall might also dissociate the outward elastic recoil forces of the lung from the inward narrowing forces of stimulated smooth muscle, allowing increased shortening (3Macklem P.T Bronchial hyporesponsiveness.Chest. 1987; 91: 189S-191SCrossref PubMed Google Scholar) or more rapid and sustained shortening (4Fredberg J.J Inouye D Miller B et al.Airway smooth muscle, tidal stretches, and dynamically determined contractile states.Am J Respir Crit Care Med. 1997; 156: 1752-1759Crossref PubMed Scopus (367) Google Scholar). Increased thickness (remodeling) of the airway wall in asthma, which is thought to result from chronic inflammation of the airway wall, is comprised of inflammatory cells (eosinophils, macrophages, T lymphocytes) and a variety of extracellular matrix proteins, including scar collagen and tenascin, as well as increased smooth muscle, epithelial goblet cells, submucosal mucous glands, and blood vessels. Inflammation and remodeling are linked by the presence of numerous inflammatory cytokines, chemokines, growth factors, and tissue metalloproteinases. The duration and severity of asthma may be related to the degree of airway remodeling (5Bai T.R Cooper J Koelmeyer T Pare P.D Weir T.D The effect of age and duration of disease on airway structure in fatal asthma.Am J Respir Crit Care Med. 2000; 162: 663-669Crossref PubMed Scopus (221) Google Scholar).Can airway remodeling be reversed by current methods of treatment? How can the effects of treatment be monitored? Although lung function, symptoms, and airway inflammation (eosinophils) respond rapidly in days or weeks to inhaled corticosteroids (6Reddel H.K Jenkins C.R Marks G.B et al.Optimal asthma control, starting with high doses of inhaled budesonide.Eur Respir J. 2000; 16: 226-235Crossref PubMed Scopus (129) Google Scholar, 7Ward C Pais M Bish R et al.Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma.Thorax. 2002; 57: 309-316Crossref PubMed Scopus (353) Google Scholar), maximum reductions in airway hyperresponsiveness take 6 or more months to achieve (6Reddel H.K Jenkins C.R Marks G.B et al.Optimal asthma control, starting with high doses of inhaled budesonide.Eur Respir J. 2000; 16: 226-235Crossref PubMed Scopus (129) Google Scholar, 7Ward C Pais M Bish R et al.Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma.Thorax. 2002; 57: 309-316Crossref PubMed Scopus (353) Google Scholar) and are thought to reflect more gradual changes in airway wall remodeling, based on biopsy studies showing that prolonged, high-dose inhaled corticosteroids, are required to reduce the thickness of the reticular basement membrane (7Ward C Pais M Bish R et al.Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma.Thorax. 2002; 57: 309-316Crossref PubMed Scopus (353) Google Scholar, 8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar). Two studies have shown a relation between reticular basement membrane thickness and airway wall thickness, including the smooth muscle (9Kasahara K Shiba K Ozawa T Okuda K Adachi M Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma.Thorax. 2002; 57: 242-246Crossref PubMed Scopus (185) Google Scholar, 10James A.L Maxwell P.S Pearce-Pinto G Elliot J.G Carroll N.G The relationship of reticular basement membrane thickness to airway wall remodeling in asthma.Am J Respir Crit Care Med. 2002; 166: 1590-1595Crossref PubMed Scopus (130) Google Scholar), but it is not known whether treatment induced reductions in the basement membranes are also associated with reduced thickness of other airway wall dimensions.In this issue of The American Journal of Medicine, Niimi et al (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) have shown that treatment over 12 weeks with inhaled beclomethasone (800 mcg/d) resulted in a substantial decrease in the thickness of the apical segmental bronchus of the right upper lobe, as assessed by computed tomographic (CT) scans. The study demonstrated that the airway wall was thicker in cases of asthma compared with controls, as shown in an earlier study by the same group that related the thickness of the airway wall on CT scan to the clinical severity of asthma (12Niimi A Matsumoto H Amitani R et al.Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices.Am J Respir Crit Care Med. 2000; 162: 1518-1523Crossref PubMed Scopus (323) Google Scholar). As noted in prior CT studies (13Awadh N Muller N.L Park C.S Abboud R.T FitzGerald J.M Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning.Thorax. 1998; 53: 248-253Crossref PubMed Scopus (188) Google Scholar), treatment did not result in a substantial change in the airway lumenal area. In contrast, patients with chronic obstructive pulmonary disease (COPD) show more modest increases in airway wall thickness but reduced cross-sectional area of the lumen, compared with control cases (14King G.G Muller N.L Pare P.D Evaluation of airways in obstructive pulmonary disease using high- resolution computed tomography.Am J Respir Crit Care Med. 1999; 159: 992-1004Crossref PubMed Scopus (124) Google Scholar). The current study by Niimi et al (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) takes the use of CT scanning in asthma one step further––into the realms of a monitoring tool to assess the effectiveness of treatment.Monitoring the effects of treatment in asthma is entering a new phase with the realization that the use of traditional methods of monitoring, such as symptom scores, bronchodilators, and peak flows, even when performed diligently within the confines of prospective studies, are inferior to the addition of measures of airway responsiveness (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar) or sputum eosinophils (15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar) in preventing exacerbations of asthma. These measures of airway pathology likely reflect airway inflammation (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar, 15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar) or airway remodeling and altered airway wall mechanics (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar).The study by Niimi et al (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) demonstrates that the CT scan can be used to assess changes in airway wall dimensions in response to treatment in patients with asthma. They studied adults who had not previously used corticosteroids who reported symptoms for periods varying from a few months to 60 years and who had persistent symptoms described as mild, moderate, or severe. As a group, lung function was abnormal, with a mean forced expired volume of only 78% of predicted. Such patients would be expected to show considerable improvements in symptoms and lung function over a 12-week period (6Reddel H.K Jenkins C.R Marks G.B et al.Optimal asthma control, starting with high doses of inhaled budesonide.Eur Respir J. 2000; 16: 226-235Crossref PubMed Scopus (129) Google Scholar, 8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar) and therefore would be likely to maximize the sensitivity of the CT to detect changes in airway wall dimensions. Although there was a considerable reduction in airway wall thickness in the asthma patients, the mean airway wall thickness remained substantially greater than that of the control group. It is possible that higher doses of treatment or a longer treatment period would have produced greater changes in airway wall thickness. Both the change in airway wall thickness with treatment and the post-treatment airway wall thickness were related to the duration of asthma. Assuming these observations to be independent (which is not assured from the statistical analyses), these findings support the notion that the degree of airway remodeling in asthma is related to the duration of the disease (5Bai T.R Cooper J Koelmeyer T Pare P.D Weir T.D The effect of age and duration of disease on airway structure in fatal asthma.Am J Respir Crit Care Med. 2000; 162: 663-669Crossref PubMed Scopus (221) Google Scholar, 12Niimi A Matsumoto H Amitani R et al.Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices.Am J Respir Crit Care Med. 2000; 162: 1518-1523Crossref PubMed Scopus (323) Google Scholar).Niimi et al speculate that the reduced airway wall thickness following treatment is due to a responsive inflammatory element, and that persistent remodeling is due to an “unresponsive component.” Herein lies the limitation of high resolution CT measurements of airway wall thickness: thickening due to airway wall or adventitial edema or increased mucus on the mucosal surface cannot be differentiated from thickening due to other causes, such as alterations in the extracellular matrix and the content of collagen and elastin. The latter may still be responsive to treatment although at a slower rate. The usefulness of CT scanning to monitor airway pathology in response to treatment might be explored further if it were combined with measurements that are specific for airway remodeling and inflammation, an answer that will require longer-term studies of the changes in airway wall thickness with treatment, combined with serial measurements of airway remodeling and inflammation.Patients such as those in the Niimi study (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) typically would be treated with inhaled corticosteroids. The sensitivity and usefulness of the CT scan in monitoring patients already on inhaled corticosteroids and in whom small adjustments in dose are being made is also to be determined. The sensitivity and reproducibility of measurements of airway dimensions from high resolution CT are likely to improve with hardware and image analysis. The current study was done with 3-mm–thick slices, most likely (although not stated) with a single slice scanner and of a single bronchus. The image analysis technique was an objective computer analysis, validated on an artificial airway phantom. Multi-slice scanners allow faster scanning (less movement artifact) of a volumetric dataset at higher resolution (1.25-mm slice thickness) and at lower radiation exposure. This newer method will allow more airways to be studied from regions other than the apical segmental bronchus of the right upper lobe. Even greater resolution, scanning speed, and coverage will be possible with the next generation of flat panel detectors. Image analysis techniques also need to be improved to make full use of such three-dimensional datasets and, ideally, to be validated using more realistic ‘gold standards’ (i.e., fixed lung specimens rather than artificial tubes [16King G.G Muller N.L Whittall K.P Xiang Q.S Pare P.D An analysis algorithm for measuring airway lumen and wall areas from high-resolution computed tomographic data.Am J Respir Crit Care Med. 2000; 161: 574-580Crossref PubMed Scopus (131) Google Scholar]). Such developments and innovations may allow airway measurements to be more repeatable, thereby improving the sensitivity of CT scans to detect small changes, and would allow the study of airways of different sizes and different sites consistent with the heterogeneity of airway caliber that is characteristic of asthma (17Verbanck S Schuermans D Paiva M Vincken W Nonreversible conductive airway ventilation heterogeneity in mild asthma.J Appl Physiol. 2003; 94: 1380-1386PubMed Google Scholar).In a similar fashion to the monitoring studies of Sont et al (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar) and Green et al (15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar), CT may also have a role in setting long-term goals of treatment. In this regard, the study of Green et al (15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar) showed that by monitoring sputum eosinophils, the dose of inhaled corticosteroid could be reduced in some patients and should be increased in others, resulting in no increase in average dose while reducing the risk of exacerbation for the group as a whole. Similarly, CT scanning may be useful in determining which patients might benefit from more treatment (continuing reductions in airway wall thickness) or less treatment (stable wall thickness). Although answers to these questions lay ahead, the study of Niimi (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) has broken new ground in establishing the use of the CT to monitor the effects of therapy in asthma. Patients with asthma present with wheeze, cough, chest tightness, and shortness of breath. These symptoms result from excessive airway lumenal narrowing in response to shortening of the circumferential smooth muscle (1Moreno R.H Hogg J.C Pare P.D Mechanics of airway narrowing.Am Rev Respir Dis. 1986; 133: 1171-1180PubMed Google Scholar). Mechanisms of excessive airway narrowing include increased shortening of smooth muscle, due to an imbalance between the ability of the muscle to develop force and the loads opposing shortening and an exaggeration of the effects of muscle shortening on the airway lumen area due to increased thickness of the airway wall between the airway smooth muscle and the lumen (1Moreno R.H Hogg J.C Pare P.D Mechanics of airway narrowing.Am Rev Respir Dis. 1986; 133: 1171-1180PubMed Google Scholar). The increased thickness of the airway wall observed in severe and mild cases of asthma (2Carroll N Elliot J Morton A James A The structure of large and small airways in nonfatal and fatal asthma.Am Rev Respir Dis. 1993; 147: 405-410Crossref PubMed Scopus (649) Google Scholar) could account for excessive airway narrowing in the presence of normal (or increased) smooth muscle shortening (1Moreno R.H Hogg J.C Pare P.D Mechanics of airway narrowing.Am Rev Respir Dis. 1986; 133: 1171-1180PubMed Google Scholar). Increased thickness of the airway wall might also dissociate the outward elastic recoil forces of the lung from the inward narrowing forces of stimulated smooth muscle, allowing increased shortening (3Macklem P.T Bronchial hyporesponsiveness.Chest. 1987; 91: 189S-191SCrossref PubMed Google Scholar) or more rapid and sustained shortening (4Fredberg J.J Inouye D Miller B et al.Airway smooth muscle, tidal stretches, and dynamically determined contractile states.Am J Respir Crit Care Med. 1997; 156: 1752-1759Crossref PubMed Scopus (367) Google Scholar). Increased thickness (remodeling) of the airway wall in asthma, which is thought to result from chronic inflammation of the airway wall, is comprised of inflammatory cells (eosinophils, macrophages, T lymphocytes) and a variety of extracellular matrix proteins, including scar collagen and tenascin, as well as increased smooth muscle, epithelial goblet cells, submucosal mucous glands, and blood vessels. Inflammation and remodeling are linked by the presence of numerous inflammatory cytokines, chemokines, growth factors, and tissue metalloproteinases. The duration and severity of asthma may be related to the degree of airway remodeling (5Bai T.R Cooper J Koelmeyer T Pare P.D Weir T.D The effect of age and duration of disease on airway structure in fatal asthma.Am J Respir Crit Care Med. 2000; 162: 663-669Crossref PubMed Scopus (221) Google Scholar). Can airway remodeling be reversed by current methods of treatment? How can the effects of treatment be monitored? Although lung function, symptoms, and airway inflammation (eosinophils) respond rapidly in days or weeks to inhaled corticosteroids (6Reddel H.K Jenkins C.R Marks G.B et al.Optimal asthma control, starting with high doses of inhaled budesonide.Eur Respir J. 2000; 16: 226-235Crossref PubMed Scopus (129) Google Scholar, 7Ward C Pais M Bish R et al.Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma.Thorax. 2002; 57: 309-316Crossref PubMed Scopus (353) Google Scholar), maximum reductions in airway hyperresponsiveness take 6 or more months to achieve (6Reddel H.K Jenkins C.R Marks G.B et al.Optimal asthma control, starting with high doses of inhaled budesonide.Eur Respir J. 2000; 16: 226-235Crossref PubMed Scopus (129) Google Scholar, 7Ward C Pais M Bish R et al.Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma.Thorax. 2002; 57: 309-316Crossref PubMed Scopus (353) Google Scholar) and are thought to reflect more gradual changes in airway wall remodeling, based on biopsy studies showing that prolonged, high-dose inhaled corticosteroids, are required to reduce the thickness of the reticular basement membrane (7Ward C Pais M Bish R et al.Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma.Thorax. 2002; 57: 309-316Crossref PubMed Scopus (353) Google Scholar, 8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar). Two studies have shown a relation between reticular basement membrane thickness and airway wall thickness, including the smooth muscle (9Kasahara K Shiba K Ozawa T Okuda K Adachi M Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma.Thorax. 2002; 57: 242-246Crossref PubMed Scopus (185) Google Scholar, 10James A.L Maxwell P.S Pearce-Pinto G Elliot J.G Carroll N.G The relationship of reticular basement membrane thickness to airway wall remodeling in asthma.Am J Respir Crit Care Med. 2002; 166: 1590-1595Crossref PubMed Scopus (130) Google Scholar), but it is not known whether treatment induced reductions in the basement membranes are also associated with reduced thickness of other airway wall dimensions. In this issue of The American Journal of Medicine, Niimi et al (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) have shown that treatment over 12 weeks with inhaled beclomethasone (800 mcg/d) resulted in a substantial decrease in the thickness of the apical segmental bronchus of the right upper lobe, as assessed by computed tomographic (CT) scans. The study demonstrated that the airway wall was thicker in cases of asthma compared with controls, as shown in an earlier study by the same group that related the thickness of the airway wall on CT scan to the clinical severity of asthma (12Niimi A Matsumoto H Amitani R et al.Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices.Am J Respir Crit Care Med. 2000; 162: 1518-1523Crossref PubMed Scopus (323) Google Scholar). As noted in prior CT studies (13Awadh N Muller N.L Park C.S Abboud R.T FitzGerald J.M Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning.Thorax. 1998; 53: 248-253Crossref PubMed Scopus (188) Google Scholar), treatment did not result in a substantial change in the airway lumenal area. In contrast, patients with chronic obstructive pulmonary disease (COPD) show more modest increases in airway wall thickness but reduced cross-sectional area of the lumen, compared with control cases (14King G.G Muller N.L Pare P.D Evaluation of airways in obstructive pulmonary disease using high- resolution computed tomography.Am J Respir Crit Care Med. 1999; 159: 992-1004Crossref PubMed Scopus (124) Google Scholar). The current study by Niimi et al (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) takes the use of CT scanning in asthma one step further––into the realms of a monitoring tool to assess the effectiveness of treatment. Monitoring the effects of treatment in asthma is entering a new phase with the realization that the use of traditional methods of monitoring, such as symptom scores, bronchodilators, and peak flows, even when performed diligently within the confines of prospective studies, are inferior to the addition of measures of airway responsiveness (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar) or sputum eosinophils (15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar) in preventing exacerbations of asthma. These measures of airway pathology likely reflect airway inflammation (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar, 15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar) or airway remodeling and altered airway wall mechanics (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar). The study by Niimi et al (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) demonstrates that the CT scan can be used to assess changes in airway wall dimensions in response to treatment in patients with asthma. They studied adults who had not previously used corticosteroids who reported symptoms for periods varying from a few months to 60 years and who had persistent symptoms described as mild, moderate, or severe. As a group, lung function was abnormal, with a mean forced expired volume of only 78% of predicted. Such patients would be expected to show considerable improvements in symptoms and lung function over a 12-week period (6Reddel H.K Jenkins C.R Marks G.B et al.Optimal asthma control, starting with high doses of inhaled budesonide.Eur Respir J. 2000; 16: 226-235Crossref PubMed Scopus (129) Google Scholar, 8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar) and therefore would be likely to maximize the sensitivity of the CT to detect changes in airway wall dimensions. Although there was a considerable reduction in airway wall thickness in the asthma patients, the mean airway wall thickness remained substantially greater than that of the control group. It is possible that higher doses of treatment or a longer treatment period would have produced greater changes in airway wall thickness. Both the change in airway wall thickness with treatment and the post-treatment airway wall thickness were related to the duration of asthma. Assuming these observations to be independent (which is not assured from the statistical analyses), these findings support the notion that the degree of airway remodeling in asthma is related to the duration of the disease (5Bai T.R Cooper J Koelmeyer T Pare P.D Weir T.D The effect of age and duration of disease on airway structure in fatal asthma.Am J Respir Crit Care Med. 2000; 162: 663-669Crossref PubMed Scopus (221) Google Scholar, 12Niimi A Matsumoto H Amitani R et al.Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices.Am J Respir Crit Care Med. 2000; 162: 1518-1523Crossref PubMed Scopus (323) Google Scholar). Niimi et al speculate that the reduced airway wall thickness following treatment is due to a responsive inflammatory element, and that persistent remodeling is due to an “unresponsive component.” Herein lies the limitation of high resolution CT measurements of airway wall thickness: thickening due to airway wall or adventitial edema or increased mucus on the mucosal surface cannot be differentiated from thickening due to other causes, such as alterations in the extracellular matrix and the content of collagen and elastin. The latter may still be responsive to treatment although at a slower rate. The usefulness of CT scanning to monitor airway pathology in response to treatment might be explored further if it were combined with measurements that are specific for airway remodeling and inflammation, an answer that will require longer-term studies of the changes in airway wall thickness with treatment, combined with serial measurements of airway remodeling and inflammation. Patients such as those in the Niimi study (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) typically would be treated with inhaled corticosteroids. The sensitivity and usefulness of the CT scan in monitoring patients already on inhaled corticosteroids and in whom small adjustments in dose are being made is also to be determined. The sensitivity and reproducibility of measurements of airway dimensions from high resolution CT are likely to improve with hardware and image analysis. The current study was done with 3-mm–thick slices, most likely (although not stated) with a single slice scanner and of a single bronchus. The image analysis technique was an objective computer analysis, validated on an artificial airway phantom. Multi-slice scanners allow faster scanning (less movement artifact) of a volumetric dataset at higher resolution (1.25-mm slice thickness) and at lower radiation exposure. This newer method will allow more airways to be studied from regions other than the apical segmental bronchus of the right upper lobe. Even greater resolution, scanning speed, and coverage will be possible with the next generation of flat panel detectors. Image analysis techniques also need to be improved to make full use of such three-dimensional datasets and, ideally, to be validated using more realistic ‘gold standards’ (i.e., fixed lung specimens rather than artificial tubes [16King G.G Muller N.L Whittall K.P Xiang Q.S Pare P.D An analysis algorithm for measuring airway lumen and wall areas from high-resolution computed tomographic data.Am J Respir Crit Care Med. 2000; 161: 574-580Crossref PubMed Scopus (131) Google Scholar]). Such developments and innovations may allow airway measurements to be more repeatable, thereby improving the sensitivity of CT scans to detect small changes, and would allow the study of airways of different sizes and different sites consistent with the heterogeneity of airway caliber that is characteristic of asthma (17Verbanck S Schuermans D Paiva M Vincken W Nonreversible conductive airway ventilation heterogeneity in mild asthma.J Appl Physiol. 2003; 94: 1380-1386PubMed Google Scholar). In a similar fashion to the monitoring studies of Sont et al (8Sont J.K Willems L.N Bel E.H van Krieken J.H Vandenbroucke J.P Sterk P.J Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group.Am J Respir Crit Care Med. 1999; 159: 1043-1051Crossref PubMed Scopus (817) Google Scholar) and Green et al (15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar), CT may also have a role in setting long-term goals of treatment. In this regard, the study of Green et al (15Green R.H Brightling C.E McKenna S et al.Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.Lancet. 2002; 360: 1715-1721Abstract Full Text Full Text PDF PubMed Scopus (1479) Google Scholar) showed that by monitoring sputum eosinophils, the dose of inhaled corticosteroid could be reduced in some patients and should be increased in others, resulting in no increase in average dose while reducing the risk of exacerbation for the group as a whole. Similarly, CT scanning may be useful in determining which patients might benefit from more treatment (continuing reductions in airway wall thickness) or less treatment (stable wall thickness). Although answers to these questions lay ahead, the study of Niimi (11Niimi et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004:116:725–731Google Scholar) has broken new ground in establishing the use of the CT to monitor the effects of therapy in asthma.