Objectives

1. To understand how to estimate airway dimensions in patients with asthma and COPD.
2. To understand the characteristics of airway dimensions estimated using CT in patients with asthma and COPD.
3. To understand the airway dimensions and other parameters in patients with COPD.

Abbreviations

AHR = airway hyperresponsiveness; Ai = airway luminal area ; Ao = total airway area ; BSA = body surface area; DL = largest luminal diameter; DS = smallest luminal diameter perpendicular to DL; ECP = eosinophil cationic protein ; HU = Hounsfield unit; LAA = low-attenuation area; r = correlation coefficient ; T = airway wall thickness; WA = wall area

Asthma and COPD are the most prevalent of lung diseases, and they contribute an enormous burden of morbidity in North America and globally.^1,2 In both disorders, environmental pathogens such as allergens, viruses, and bacteria as well as personal, occupational, and atmospheric exposures cause an exaggerated immune/inflammatory response in genetically susceptible individuals.³ The inflammatory response leads to airway wall thickening, which contributes to airway narrowing. Airway wall thickening results from inflammatory changes, such as edema and inflammatory cell infiltration, and from structural changes, such as mucous gland hyperplasia, reticular basement membrane thickening, vascular proliferation, and airway smooth muscle hypertrophy and hyperplasia.^4-7

Recently, CT has been used to measure airway wall dimensions. Patients with asthma have thicker airways on CT scans than do healthy control individuals, and the degree of thickening is related to the severity of disease and airflow obstruction.^8-13 Patients with COPD also have thicker airways, and airway wall thickness and degree of emphysema detected by a low-attenuation area (LAA) on CT can independently explain the airflow limitation of COPD.¹⁴

The objectives of this review are (1) to describe methods of estimating airway dimensions using CT images, and (2) to present the characteristics of airway dimensions in patients with asthma and COPD.

Methods

CT Scanning

For airway measurement, thin-section , low-dose helical scans are recommended¹⁵ rather than conventional CT scans; this allows the clinician to more easily obtain the optimal slice to be measured as well as allowing for longitudinal study of the effect of treatment on airway wall thickness. Such studies require comparison of scans at identical airway levels pre- and postintervention in each patient, and an unacceptably high radiation dose would be required if conventional CT scanning were used. The most suitable approach is to measure airway wall dimensions in the apical bronchus of the right upper lobe; this site has a more convenient orientation for obtaining a cross-sectional view of the airway, and the outer perimeter of the airway is not abutted by vessels or other bronchi. No contrast media should be used. The slice to be used for measurement must be selected at the main trunk of the bronchus; care must be taken to avoid oblique orientation, branching from the upper lobe bronchus, branching into the subsegments of the apical bronchus, and technical artifacts.

Measurement of Airway Dimension

There are two ways to measure the airway dimensions: (1) the manual tracing method¹⁵ and (2) semiautomatic digital analysis.¹⁴

Manual Tracing Method : The most appropriate window level is -450 Hounsfield units (HU) . A window width of 1,500 HU should be used because narrower widths cause less-than-optimal visualization of anatomic landmarks at the -450 HU level.^11,15 Regions of interest are traced manually using a mouse at the workstation, along the internal perimeter (the luminal border of the airway) and the external perimeter (the parenchymal border). When a vessel abuts the airway's external perimeter, an extrapolated line is traced on the assumption that airway wall thickness is constant throughout the areas of vascular contact. Airway luminal area (Ai) and total airway area (Ao) in mm² are determined automatically. Both airway luminal area and Ao in each airway are measured five times and the readings averaged. Airway wall area is calculated as Ao minus Ai . The percentage wall area (WA) was calculated as ( WA /Ao)/100. Because Ai and WA may be affected by body size,¹⁵ airway luminal area and airway wall area corrected by body surface area (BSA) [Ai/BSA and WA /BSA, in mm² /m² ] are also calculated as indices of airway wall dimensions. The largest luminal diameter (DL) and the smallest luminal diameter perpendicular to DL (DS) are measured. Airways with a DL/DS ratio of ≥1.5 are not included because they are considered to be obliquely oriented.¹¹

Semiautomatic Digital Analysis : The trunk of the apical bronchus of the right upper lobe is evaluated. Images containing the apical bronchus to the right upper lobe are selected by a consensus reading of pulmonologists. With the bronchus identified, the following parameters are measured automatically on the computer (Fig 1): airway luminal area, short radius and long radius of the lumen, and airway wall thickness (T). T he following procedures have been used: (1) The lumen of the bronchus was identified using a threshold of -500.¹⁶ The area of the lumen was considered as Ai. (2) The short radius and long radius were defined as the shortest and longest distances from the centroid point of the lumen to the edge. (3) From the centroid point of the lumen, 128 rays fanning out over a 360-degree range were examined to determine T along the rays using the "full-width at half-maximum" principle.^17,18 (4) Rays that projected onto the adjacent vessel were excluded. T was calculated from the nonexcluded rays.

Findings in Asthma

CT findings, including airway wall thickening, have been evaluated in asthmatic patients.¹⁹ However, most interpretations were subjective,^19,20 and only a few studies have used CT to quantitatively analyze airway wall thickness in patients with asthma.^8-10 Okazawa and colleagues⁹ and Awadh and associates¹⁰ have shown that the airways of asthmatic patients are thicker than those of normal control subjects, whereas Boulet and colleagues⁸ did not show such a difference. The presence and significance of airway wall thickening as assessed by CT in asthmatic patients thus remains to be clarified.

Recently, Niimi and coworkers¹¹ analyzed 81 asthmatic patients (7 intermittent, 13 mild persistent, 39 moderate persistent, and 22 severe persistent) and compared them with 28 healthy volunteers. The representative CT images are shown in Figure 2. They found that the airway wall area was increased in patients with asthma without a decrease in airway luminal area. Airway wall area correlated positively with the duration and clinical severity of asthma (Fig 3), and negatively with FEV₁ (% predicted), FEV₁ /FVC (%), and forced expiratory flow over the middle half of the vital capacity (% predicted). Airway wall area percentage (the percent ratio of wall area to airway area) was negatively related to FEV₁ (% predicted). Matsumoto and coworkers²¹ measured serum eosinophil cationic protein (ECP) levels , which reflect ongoing eosinophilic airway inflammation and are used as a marker for asthma activity, in 113 asthmatic patients during exacerbation. However, ECP levels were not elevated in some asthmatic patients, although they were symptomatic. Such patients with low ECP levels were significantly older, had longer disease duration, and had lower serum IgE levels. They had larger airway wall thickness than those with higher ECP levels. Thus, mechanisms other than eosinophilic inflammation, such as airway remodeling, may be involved in asthma exacerbation in these patients.

The relationship between airway wall thickness and inducible airway narrowing or airway hyperresponsiveness (AHR) has rarely been investigated. Boulet et al⁸ and Little et al¹³ evaluated airway wall thickness, as assessed by CT, and AHR in asthmatic patients. AHR was measured as the provocative concentration of methacholine⁸ or histamine¹³ that produced a 20% fall in FEV₁ . One study demonstrated a positive correlation of AHR with airway wall thickness in a subgroup of patients, 8 whereas the other found no significant relationship.¹³ Niimi and coworkers²² addressed these inconsistent findings by studying the relationship between airway wall thickness, assessed by CT, and AHR, evaluated by continuous inhalation of methacholine²³ in stable asthmatics using (n = 23) or not using (n = 22) inhaled steroids. As   using the provocative concentration of methacholine that produces a 20% fall in FEV₁ as the sole index of AHR, the latter method can be used to separately evaluate the two distinct and possibly independent components of AHR: (1) airway sensitivity and (2) airway reactivity or exaggerated airway narrowing.^24,25 Airway hypersensitivity means the leftward shift of the methacholine–respiratory resistance dose-response curve. Airway hyperreactivity is marked by a steeper slope of the dose-response curve. In both groups of patients, airway sensitivity was not related to airway reactivity. Airway sensitivity was related to eosinophil count in induced sputum [correlation coefficient (r) = 0.57 in the steroid group and r = 0.49 in the no-steroid group], but not to airway wall thickness. In contrast, airway reactivity was negatively correlated with airway wall thickness (r = –0.56 and r = –0.55) but not with eosinophil count (Fig 4). These results suggest that airway wall thickening attenuates airway reactivity in asthmatic patients. These findings may suggest a relationship between pathophysiology and airway remodeling in asthma.

Findings in COPD

Nakano and colleagues¹⁴ measure d the dimensions of the apical segmental bronchus in 114 smokers (94 patients with COPD and 20 asymptomatic control subjects). They found that the airway luminal area was smaller and airway WA percentage was bigger in COPD patients than in asymptomatic control subjects ( Table 1 ). They tested whether the airway WA percentage added value to the prediction of pulmonary function tests beyond a high-resolution CT estimate of the severity of emphysema, ie , the percentage of LAA compared with total lung area.. Although both airway WA percentage and LAA percentage correlated with measurements of lung function, the combination of airway WA percentage and LAA percentage improved the estimate of pulmonary function abnormalities. In a multivariate model, the authors found that they could more accurately predict FEV₁ , FVC, FEV₁ /FVC, and peak expiratory flow, but not diffusing capacity of the lung for carbon monoxide, when both the estimate of airway wall thickening and the extent of LAAs were included in a statistical model¹⁴ (Table 2). They also found that by using LAA percentage and airway WA percentage, they could divide patients with COPD into groups who had either predominant loss of lung attenuation or thickening and narrowing of the apical segmental bronchus (Fig 5). Although many subjects had both decreased lung attenuation consistent with emphysema and airway wall thickening, there were individuals with similar degrees of obstruction whose abnormalities appeared to be predominantly the result of airway remodeling and others in whom abnormalities appeared to be predominantly related to the loss of lung parenchyma. Interestingly, Nakano et al¹⁴ also found that the luminal area was related to FEV₁, while Niimi et al¹¹ failed to find any relationship between the luminal area and the severity of asthma. The different patterns of remodeling shown by these two studies may reflect fundamental differences in the inflammatory processes in asthma and COPD and could influence the reversibility of the airway narrowing.

Summary

Asthma and COPD are the most prevalent of lung diseases, and they contribute an enormous burden of morbidity in North America and globally. Recently, CT has been used to measure airway wall dimensions. Thin-section helical scans, rather than conventional CT scans, are recommended for measurement . The most suitable site for measuring airway wall dimensions is the apical bronchus of the right upper lobe because it is better oriented for obtaining a cross-sectional view of the airway, and the airway's outer perimeter there is not abutted by vessels or other bronchi. No contrast media should be used. Semiautomatic digital analysis is superior to the manual tracing method of measuring the airway dimensions because it saves time and labor, is more objective, and has better reproducibility.

In patients with asthma, the findings that have been obtained with this method are as follows: (1) Airway WA was increased without a decrease in airway luminal area. (2) Airway WA was correlated positively with the duration and severity of asthma. (3) Airway sensitivity was related to sputum eosinophil count, but not to airway wall thickness. (4) Airway reactivity was negatively correlated with airway wall thickness but not with eosinophil count.

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