Portal de Periódicos da CAPES

Evaluating small-airways disease in asthmatic patients: The utility of quantitative computed tomography

2016; Elsevier BV; Volume: 139; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2016.11.010

1097-6825

Donald P. Tashkin, Hyun J. Kim, Michelle Zeidler, Eric C. Kleerup, Jonathan Goldin,

Tracheal and airway disorders

The tracheobronchial tree comprises a branching system of airways, beginning with the trachea, in which each airway divides mostly dichotomously into 2 smaller airways of progressively smaller diameter and, in most cases, shorter length, down to the smallest airway (a respiratory bronchiole) before terminating after approximately 23 divisions in the distal air sacs and alveoli. Historically, the lower respiratory tract has been divided into large and small airways, the latter defined as airways of 2 mm in diameter or smaller and corresponding to approximately the seventh or eighth generation and beyond of branching airways. In view of the exponential increase in the number of airways with each successive generation, most of the tracheobronchial tree is comprised of small airways, the total cross-sectional area of which is much greater than that of the larger airways, resulting in a relatively low resistance to airflow in the healthy lung. Asthma is characterized by inflammation that involves both the large and small airways. In patients with relatively mild asthma, inflammatory changes in the small airways might not be clinically or even physiologically obvious because of the very large numbers of these airways available for flow, thus explaining their characterization as the "quiet zone." In contrast, in patients with severe asthma or even those with milder asthma, especially during sleep or during severe exacerbations, the small airways, by virtue of their relatively narrow diameter and the inflammatory changes therein, are more vulnerable to further and at times nearly complete luminal narrowing caused by worsening inflammatory infiltration, mucus accumulation, and smooth muscle constriction. Thus they can become the predominant site of airflow resistance, with clinically significant and at times quite serious and potentially even fatal consequences. Because of their clinical and prognostic importance in patients with all severities of asthma, there is much interest in assessing the extent and nature of small-airways abnormality, to which end a variety of physiologic, endoscopic, and imaging techniques have been applied. Among the assortment of imaging techniques used,1Castro M. Fain S.B. Hoffman E.A. Gierada D. Erzurum S.C. Wenzel S. Lung imaging in asthma: the picture is clearer.J Allergy Clin Immunol. 2011; 128: 467-478Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar quantitative computed tomography (QCT) has been increasingly common. With the advent of fast multidetector scanners and techniques for low-dose computed tomographic (CT) scan acquisition, thoracic QCT, although not capable of visualizing the small airways directly because of inadequate resolution, has nonetheless enabled investigators to assess the structure of the small airways indirectly.2Hartley R. Baldi S. Brightling C. Gupta S. Novel imaging approaches in adult asthma and their clinical potential.Expert Rev Clin Immunol. 2015; 11: 147-162Crossref Scopus (6) Google Scholar Small-airways dysfunction results in maldistribution of ventilation, with reduced ventilation in regions of the lung leading to reflex vasoconstriction and thereby resulting in regional decreases in lung attenuation on inspiratory CT images. The heterogeneity of lung attenuation on inspiratory CT scans is accentuated in expiratory scans because of regional differences in small-airways closure with visual evidence of a mosaic or geographic pattern of gas trapping.3Stern E.J. Swensen S.J. Hartman T.E. Frank M.S. CT mosaic pattern of lung attenuation: distinguishing difference causes.AJR Am J Roentgenol. 1995; 165: 813-816Crossref PubMed Scopus (118) Google Scholar The extent of low-attenuation areas on expiratory CT scans can be quantitatively assessed by using lung densitometry with calculation of the percentage of pixels in the lung parenchyma having an attenuation value of less than a predetermined threshold. Different thresholds of optical lung density for quantifying gas trapping in asthmatic patients have been developed, including the following: percentage of pixels of −850 Hounsfield units (HU) lung attenuation as a threshold at functional residual capacity4Busacker A. Newell Jr., J.D. Keefe T. Hoffman E.A. Granroth J.C. Castro M. et al.A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.Chest. 2009; 135: 48-56Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar; percentage of pixels of −900 HU as a threshold at full expiration5Newman K.B. Lynch D.A. Newman L.S. Ellegood D. Newell Jr., J.D. Quantitative computed tomography detects air trapping due to asthma.Chest. 1994; 106: 105-109Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar; mean lung density expiratory to inspiratory ratio6Gono H. Fujimoto K. Kawakami S. Kubo K. Evaluation of airway wall by HRCT in asymptomatic asthma.Eur Respir J. 2003; 22: 965-971Crossref PubMed Scopus (126) Google Scholar; difference between inspiratory and expiratory lung attenuation7Tunon-de-Lara J.M. Laurent F. Giraud V. Perez T. Aguilaniu B. Meziane H. et al.Air trapping in mild and moderate asthma: effect of inhaled corticosteroids.J Allergy Clin Immunol. 2007; 119: 583-590Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar; and lowest 10th percentile on the cumulative frequency distribution lung attenuation curve.8Goldin J.G. McNitt-Gray M.F. Sorenson S.M. Johnson T.D. Dauphinee B. Kleerup E.C. et al.Airway hyperreactivity: assessment with helical thin-section CT.Radiology. 1998; 208: 321-329Crossref PubMed Scopus (95) Google Scholar These measures can be applied to a whole lung, lobe, or anatomic segment (see below). Worsening gas trapping in asthmatic patients, as assessed by means of CT as a marker of small-airways involvement, has been associated with airway hyperresponsiveness,5Newman K.B. Lynch D.A. Newman L.S. Ellegood D. Newell Jr., J.D. Quantitative computed tomography detects air trapping due to asthma.Chest. 1994; 106: 105-109Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 8Goldin J.G. McNitt-Gray M.F. Sorenson S.M. Johnson T.D. Dauphinee B. Kleerup E.C. et al.Airway hyperreactivity: assessment with helical thin-section CT.Radiology. 1998; 208: 321-329Crossref PubMed Scopus (95) Google Scholar disease duration,4Busacker A. Newell Jr., J.D. Keefe T. Hoffman E.A. Granroth J.C. Castro M. et al.A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.Chest. 2009; 135: 48-56Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 7Tunon-de-Lara J.M. Laurent F. Giraud V. Perez T. Aguilaniu B. Meziane H. et al.Air trapping in mild and moderate asthma: effect of inhaled corticosteroids.J Allergy Clin Immunol. 2007; 119: 583-590Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar airflow limitation,6Gono H. Fujimoto K. Kawakami S. Kubo K. Evaluation of airway wall by HRCT in asymptomatic asthma.Eur Respir J. 2003; 22: 965-971Crossref PubMed Scopus (126) Google Scholar, 9Ueda T. Niimi A. Matsumoto H. Takemura M. Hirai T. Yamaguchi M. et al.Role of small airways in asthma: investigation using high-resolution computed tomography.J Allergy Clin Immunol. 2006; 118: 1019-1025Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar and asthma severity.4Busacker A. Newell Jr., J.D. Keefe T. Hoffman E.A. Granroth J.C. Castro M. et al.A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.Chest. 2009; 135: 48-56Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 9Ueda T. Niimi A. Matsumoto H. Takemura M. Hirai T. Yamaguchi M. et al.Role of small airways in asthma: investigation using high-resolution computed tomography.J Allergy Clin Immunol. 2006; 118: 1019-1025Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar In addition, QCT has been used to evaluate the effect of therapeutic interventions with inhaled corticosteroids7Tunon-de-Lara J.M. Laurent F. Giraud V. Perez T. Aguilaniu B. Meziane H. et al.Air trapping in mild and moderate asthma: effect of inhaled corticosteroids.J Allergy Clin Immunol. 2007; 119: 583-590Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 8Goldin J.G. McNitt-Gray M.F. Sorenson S.M. Johnson T.D. Dauphinee B. Kleerup E.C. et al.Airway hyperreactivity: assessment with helical thin-section CT.Radiology. 1998; 208: 321-329Crossref PubMed Scopus (95) Google Scholar and other drugs10Zeidler M.R. Kleerup E.C. Goldin J.C. Kim H.J. Truong D.A. Simmons M.D. et al.Montelukast improves regional air-trapping due to small airways obstruction in asthma.Eur Respir J. 2006; 27: 307-315Crossref PubMed Scopus (91) Google Scholar and of exposure to constrictor stimuli and aeroallergens on the extent of small-airways dysfunction in asthmatic patients.8Goldin J.G. McNitt-Gray M.F. Sorenson S.M. Johnson T.D. Dauphinee B. Kleerup E.C. et al.Airway hyperreactivity: assessment with helical thin-section CT.Radiology. 1998; 208: 321-329Crossref PubMed Scopus (95) Google Scholar, 11Zeidler M.R. Goldin J. Kleerup E.C. Kim H.J. Truong D.A. Gjertson D.W. et al.Small airways response to naturalistic cat allergen exposure in subjects with asthma.J Allergy Clin Immunol. 2006; 118: 705-781Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Additionally, patterns of heterogeneity and reproducibility over time have been noted by our group in these studies. Here we describe a method for visualizing the spatial heterogeneity, severity, and temporal variability of small-airways air trapping using QCT before and after exposure to a constrictor stimulus (methacholine). By using computer-aided algorithms, the lungs can be segmented to the lobar and anatomic segmental level and visualized in a 3-dimensional rendering or schematic (see Fig E1, A and B in this article's Online Repository at www.jacionline.org). The degree of air trapping before and after methacholine can be calculated for each lobe and segment by generating a cumulative frequency distribution curve of the percentage of pixels at each level of lung attenuation; the change (shift) in the lung attenuation curve after methacholine challenge can readily be visualized and quantitated as an indication of an increase or decrease in air trapping (Fig E1, C). The spatial heterogeneity of the patterns of abnormally low attenuation (areas with percentage of pixels <−860 HU) can be classified as lobar (involving an entire lobe but not all lobes), mixed (involving segments or subsegments within ≥1 lobe), or diffuse (all lobes are completely involved), as illustrated in Fig 1, which shows distinct patterns of regional differences in attenuation both before and after methacholine challenge. The percentage regional increase in air trapping in response to methacholine can also be classified as mild ( 30%). This can be depicted by using a schematic color plot in which a circle of a different color and diameter can be shown for each segment, thereby readily communicating the severity and distribution of hyperresponsiveness after methacholine challenge in each segment, lobe, and lung (Fig 2). These patterns of air trapping appear to be constant over time for a given subject (see Fig E2 in this article's Online Repository at www.jacionline.org).Fig 2Coronal low-dose CT images show the different patterns of spatial distribution of air trapping defined quantitatively by means of density mask or relative area less than −860 HU. The plots show a pictorial summary of the degree of air trapping after methacholine challenge. The color and diameter of each circle summarizes the magnitude of air trapping after methacholine.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The visual depiction of the different patterns and magnitudes of regional air trapping identified by using QCT both before and after methacholine inhalation challenge, as described here, could prove to be an especially sensitive and visually effective method for assessing not only the severity of asthma but also its response to different therapeutic interventions and environmental exposures (including low-level exposures) to potential asthmagenic stimuli, such as aeroallergens and gaseous and particulate pollutants in community and indoor air that might elicit subclinical changes evident by using QCT. Fig E2The pattern and extent of low attenuation caused by air trapping appears to be repeatable from one week to the next for a given patient with clinically stable asthma of varying severity of air trapping. MCH, Methacholine.View Large Image Figure ViewerDownload Hi-res image Download (PPT)