Outcomes of Airway Remodeling in Severe Asthma

Demographics

The characteristics of the subjects in our study (Table 1) demonstrated that those with severe persistent asthma, on average, were older, reported more frequent symptoms of allergies, and had elevated levels of IgE, increased airway hyperresponsiveness, and decreased baseline FEV1 percent predicted compared to patients with mild-to-moderate asthma and healthy subjects. Subjects in the biopsy subset were representative of the overall cohort (Table 1) with the exception that patients with mild-to-moderate asthma had an earlier onset of asthma (11.6 vs 13 years, respectively; p = 0.01) and a greater number of emergency department visits within the last 12 months (50% vs 5.6%, respectively; p = 0.02).

MDCT Scan Airway WT/WA/LA

There was no significant difference in average WT among the groups. To account for differences in airway size, we calculated the WT% (Fig 1) for the labeled airways in each subject. Patients with severe asthma had significantly greater WT% than those with mild-to-moderate asthma and healthy subjects (Fig 2, Table 2). There was no significant difference in WT% between patients with mild-to-moderate asthma and healthy subjects. The increase in WT% inversely correlated with baseline FEV1 percent predicted (r = —0.39; p < 0.0001), and positively correlated with the change in FEV1 percent predicted post-bronchodilator therapy (r = 0.28; p = 0.002). This finding was primarily due to the relationship between WT% and FEV1 percent predicted (r = —0.47; p = 0.0003) in patients with severe asthma. There was no significant relationship between WT% and FEV1 percent predicted in patients with mild-to-moderate asthma and healthy subjects. There was no significant correlation between WT% and FEV1 PC20. More information about bronchodilator therapy you may know on Asthma Inhalers.

There was no statistically significant difference in WA among the groups. The analysis of WA% showed that patients with severe asthma had greater WA% compared to patients with mild-to-moderate asthma and healthy subjects. There was no significant difference in WA% between patients with mild-to-moder-ate asthma and healthy subjects (Fig 2, Table 2). WA% was inversely correlated with baseline FEVX percent predicted (r = —0.4; p < 0.0001), and positively correlated with change in FEV1 percent predicted post-bronchodilator therapy (r = 0.35; p < 0.0001). The correlation between WA% and baseline FEV1 percent predicted was due to the relationship in patients with severe asthma (r = —0.49; p = 0.0001). There was a significant inverse correlation between WA% with FEV1 PC20 (all asthmatic subjects: r = —0.29; p = 0.02; patients with severe asthma: r = —0.48 ; p = 0.01).

LA was not significantly different among the groups. Patients with severe asthma had a smaller LA% compared to those with mild-to-moderate asthma and healthy subjects. There was no significant difference in LA% between patients with mild-to-moderate asthma and healthy subjects (difference was not significant).

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Patients with severe asthma

Segmental MDCT Scan Comparisons

Individual airways segments were compared among the three groups in regard to WT% and WA%. WT% in a few airways and WA% in most airways were significantly greater in patients with severe asthma compared to those with mild-to-moderate asthma and healthy subjects (Table 3). Because segmental WT measurements are not independent of each other, we calculated a slope of airway WT% and WA% from the apex to the base of the lung in each individual subject. The slopes for WT% and WA% were not significantly different among the groups.

The range (ie, the minimum to maximum measurement) in airway thickness across segments per subject for WT% was 9.7 to 29.9 for healthy subjects, 9.7 to 29.6 for patients with mild-to-moderate asthma, and 9.8 to 30.1 for patients with severe asthma; for WA%, the range was 38.6 to 65.5 for healthy subjects, 38.9 to 64.7 for patients with mild-to-moderate asthma, and 39.0 to 67.3 for patients with severe asthma. The variability of WA% across segments was significantly different among groups, with the patients with severe asthma (28.3 ± 3.4) having more variability than those with mild-to-moderate asthma (25.8 ± 3.4) or healthy subjects (26.9 ± 4.0; p = 0.0035); but, this was not the case for WT% (p = 0.92). The WT% and WA% ranges in an individual’s segmental airways are highly variable and are dependent on the underlying disease status. However, if one focuses on the right upper lobe (RUL) apical segment (previously used in other studies), there was a statistically significant correlation between the RUL apical segment WA% (r = 0.75; p < 0.0001) and the WT% (r = 0.52; p < 0.0001) with all other segments (up to 19).

Severe Asthma

Multivariate Analysis of WA/WT

The variables that distinguished patients with severe asthma from those with mild-to-moderate asthma and healthy subjects included the following: age; baseline FEV1 percent predicted and FVC percent predicted; log IgE; and change in FEV1 post-bronchodilator therapy. We also found that WT% and WA% were significantly greater in patients with severe asthma compared to patients with mild-to-moderate asthma and healthy subjects. Stepwise multiple regression models used FEV1 percent predicted, WA%, and WT% as dependent variables. The only significant independent predictors of FEVj percent predicted were WT% (p = 0.0004) and group (p < 0.0001; R2 = 0.48). When WT% was the dependent variable in the stepwise regression, the significant independent correlates were FEV1 percent predicted (p < 0.0001) and history of intubation (p = 0.04; R2 = 0.415). The only significant independent correlate of WA% was FEV1 percent predicted (p < 0.0001; R2 = 0.331).

Correlation Between MDCT Scan Airway Indexes and Remodeling

The epithelial thickness ratio was positively correlated with both WT% and WA% (r = 0.47, p = 0.007; and r = 0.52, p = 0.003, respectively) [Fig 3]. The relationship between LR thickness ratio and WT% and WA% demonstrated a similar trend (r = 0.33, p = 0.07; and r = 0.33, p = 0.06, respectively). The sum of epithelial and LR ratios was also positively correlated with WT% and WA% (r = 0.46, p = 0.008; and r = 0.49, p = 0.004, respectively).

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Figure 2
Figure 2. MDCT scan images and bronchial biopsy specimens from healthy subjects and patients with severe asthma. Representative images from matching MDCT scan analyses and hematoxlyn-eosin-stained sections from an endobronchial biopsy specimen from a healthy control subject (top left, A, and top right, C) and a patient with severe asthma (bottom left, B, and bottom right, D) are demonstrated. The MDCT scan analysis was performed using the Pulmonary Workstation software (VIDA Dignostics), and a screen capture of the cross-sectional MDCT scan image is demonstrated. The hematoxylin-eosin-stained sections were obtained from endobronchial biopsy specimens that were processed as described in the “Materials and Methods” section. The epithelial layer (Epi), LR, and the basement membrane (dashed line) are indicated.

Figure 3
Figure 3. MDCT scan WT% and WA% are correlated with airway remodeling. In a subset of patients (n = 32), endobronchial biopsies were performed. Epithelial thickness was measured in micrometers and was normalized for the length of the basement membrane, resulting in an epithelial ratio. These morphometric measurements were then correlated with the radiographic indexes WT% and WA%. Top, A: WT% is correlated with epithelial thickness (r = 0.47; p = 0.007). Bottom, B: WA% is correlated with epithelial thickness (r = 0.52; p = 0.003).

Table 1—Group Characteristics

Characteristics Healthy Subjects (n = 25) Patients With Mild-to-Moderate Asthma(n = 35) Patients With Severe Asthma(n = 63) p Value!
Age4 yr 30.2 (8) 34.4 (10.6) 37.8 (13.3) 0.023
Female sex§ 16 (64) 21 (60) 37 (59) 0.9
Age at diagnosis of asthma,{ yr 13.6 (13.8) 13.4 (14.9) 0.9
Duration of asthma,! yr 20.8 (13.2) 24.4 (13.2) 0.2
Baseline FEV: < 0.001
L 3.64 2.82 1.98
% predicted 101 81 61
FEV: PC2Q,t mg/mL 1.66(1.67) 1.20(1.80) 0.051
Atopic,|| % 33.3 100 100 < 0.001
IgE4 IU 97 (174) 226 (291) 456 (697) < 0.001
Medication use, %
Any p-agonist 88.2 98.3 < 0.001
Long-acting p-agonist 41.2 91.7 < 0.001
Inhaled corticosteroid 52.9 98.3 < 0.001
Oral corticosteroid 2.9 60 < 0.001
ED or hospital visits in the past 12 mo, % 19.2 42.9 < 0.001
Hospitalizations in past 12 mo, % 0 25.9 0.002
History of intubation, % 0 20.3 0.001

Table 2—MDCT Scan Airway Measurements by Group

MDCT Scan Measurement Healthy Subjects (n = 25) Patients With Mild-to-Moderate Asthma (n = 35) Patients With Severe Asthma (n = 63) p Valuef
IHealthy Subjects vs Patients With Severe Asthma IPatients With Moderate-to-Severe Asthma vs Patients With Severe Asthma
WT, mm 1.59 (0.13) 1.66 (0.14) 1.66 (0.2) NS NS
WT%, mm 16.3(1.2) 16.5 (1.6) 17.2 (1.5) 0.031 0.014
WA, mm2 41.2 (5.5) 44.1 (6.4) 42.2 (7.4) NS NS
WA% 54.6 (2.4) 54.7 (3.3) 56.6 (2.9) 0.003 0.005
LA, mm 42.5 (7) 45.9 (9.3) 42 (9.1) NS NS
LA%, mm 45.4 (2.4) 45.3 (3.3) 43.4 (2.9) 0.005 0.003
TA, mm2 83.7(12.2) 90 (15) 84.1 (16.1) NS NS
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Table 3—MDCT Scan Air-way Wall Measurements Among Individual Airway Segments With Respect to Anatomic Location

BronchialSegment WT% WA%
IHealthy Subjects (n = 25) Patients With Mild-to-Moderate Asthma (n = 35) Patients WithSevere Asthma (n = 63) p Valuef Healthy Subjects (n = 25) Patients With Mild-to-Moderate Asthma(n = 35) Patients With Severe Asthma(n = 63) p Valuef
S vs M S vs N S vs M S vs N
L1 20.6 (3.5) 21 (4.5) 21.7(4.6) 63.2 (3.9) 62.7(4.1) 63.7 (3.0)
L2 21 (5.6) 23.3 (6.4) 20.8 (5.3) 63.8 (5.8) 60.2 (5.3) 62.2 (3.7)
L3 18.9 (7.9) 17.3 (3.6) 18.7(4.2) 57.1 (4.5) 58 (5.2) 60.3 (4.5) 0.029 0.008
L4 18.6 (5.9) 22 (5.6) 20.2 (5.3) 58.9 (4.5) 58.6 (4.7) 61.1 (4.1) 0.030 0.073
L5 19.7(4.1) 21.5 (7.8) 20.1 (4.5) 58.8 (4.4) 60.8 (3.9) 60.9 (4.3)
L6 17.2 (4.6) 17.2 (4.5) 18.3 (4.6) 57.4 (4.7) 57.6 (5.5) 60.1 (5.3) 0.027 0.031
L8 17.9 (4.3) 17.8 (5.8) 19.5 (6.2) 57.2 (3.9) 57.9 (4.8) 61.3 (4.5) 0.001 < 0.001
L9 17(3.1) 19 (5.4) 18.8 (5.0) 58.2 (3.7) 59.4 (4.6) 60.2 (4.7)
L10 17.2 (3.9) 17 (4.7) 18.8 (4.1) 57.9 (4.3) 57.4 (4.7) 60.2 (4.4) 0.006 0.041
R1 17.4 (3.4) 17.4 (3.9) 19.4 (4.0) 0.020 0.032 59 (5.3) 60 (5.5) 62.6 (4.5) 0.015 0.003
R2 18.9 (4.5) 18.8 (4.5) 19.1 (4.2) 59 (3.9) 58.3 (4.3) 60.3 (3.7) 0.027 0.076
R3 18.4 (5.3) 17.6 (3.6) 17.8 (3.4) 58.4 (3.3) 58 (5.3) 60.1 (4.5)
R4 20 (5.1) 18.5 (4.7) 21.1 (5.5) 60 (2.5) 59 (5.3) 61.4 (4.4) 0.013 0.229
R5 19.5 (4.1) 20.2 (4.3) 21.2 (4.8) 58.7 (3.0) 60.1 (4.6) 62.4 (4.0) 0.014 0.001
R6 18.3 (3.7) 19.4 (5.2) 19.4 (5.8) 58.6 (3.7) 58.3 (4.7) 58.9 (5.3)
R7 20 (4.7) 19.6 (4.0) 21.2 (5.7) 61 (4.6) 61.3 (4.0) 64.3 (4.6) 0.002 0.003
R8 19.5 (5.8) 20 (5.4) 20.1 (5.2) 60 (3.9) 59.4 (5.0) 61.2 (4.8)
R9 17.6(2.7) 18.8 (4.4) 20.1 (3.6) 0.153 0.009 59.1 (4.1) 58.6 (4.2) 61.7(3.8) 0.001 0.011
R10 18.5 (3.4) 19 (5.2) 18.8 (4.3) 59.1 (3.5) 58.7 (5.0) 60.7 (4.8)
Slopej 0.02 (0.49) 0.22 (0.44) 0.08 (0.37) 0.05 (0.46) 0.09 (0.44) -0.004 (0.38)