Rationale and Objectives
Chronic obstructive pulmonary disease is a heterogeneous disease characterized by small airway abnormality and emphysema. We hypothesized that a voxel-wise computed tomography analytic approach would identify patterns of disease progression in smokers.
Materials and Methods
We analyzed 725 smokers in spirometric GOLD stages 0-4 with two chest CTs 5 years apart. Baseline inspiration, follow-up inspiration and follow-up expiration images were spatially registered to baseline expiration so that each voxel had correspondences across all time points and respiratory phases. Voxel-wise Parametric Response Mapping (PRM) was then generated for the baseline and follow-up scans. PRM classifies lung as normal, functional small airway disease (PRM fSAD ), and emphysema (PRM EMPH ).
Results
Subjects with low baseline PRM fSAD and PRM EMPH predominantly had an increase in PRM fSAD on follow-up; those with higher baseline PRM fSAD and PRM EMPH mostly had increases in PRM EMPH . For GOLD 0 participants ( n = 419), mean 5-year increases in PRM fSAD and PRM EMPH were 0.3% for both; for GOLD 1–4 participants ( n = 306), they were 0.6% and 1.6%, respectively. Eighty GOLD 0 subjects (19.1%) had overall radiologic progression (30.0% to PRM fSAD , 52.5% to PRM EMPH , and 17.5% to both); 153 GOLD 1–4 subjects (50.0%) experienced progression (17.6% to PRM fSAD , 48.4% to PRM EMPH , and 34.0% to both). In a multivariable model, both baseline PRM fSAD and PRM EMPH were associated with development of PRM EMPH on follow-up, although this relationship was diminished at higher levels of baseline PRM EMPH .
Conclusion
A voxel-wise longitudinal PRM analytic approach can identify patterns of disease progression in smokers with and without chronic obstructive pulmonary disease.
Introduction
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by small airway abnormality and emphysema ( ). While emphysema is a prominent feature of severe disease, little is known about the stages and timeline of its progression on a radiological level. Parametric Response Mapping (PRM) analysis which incorporates information from both inspiratory and expiratory computed tomography (CT) images is one way to quantitatively assess this data. PRM captures the change in lung density between matched inspiratory and expiratory images ( ), thereby enabling the distinction between normal lung parenchyma (PRM NORM ), emphysema (PRM EMPH ), and non-emphysematous air trapping referred to as functional small airway disease (PRM fSAD ).
However, the analysis of longitudinal quantitative CT data is challenging and optimal methods have not been firmly established, particularly for PRM. Here we conduct an analysis of a large multicenter study of current and former smokers to characterize changes in PRM fSAD and PRM EMPH over 5 years of follow-up using voxel-wise coregistration of the baseline and follow-up images to characterize patterns of progression in smokers with and without COPD. We limited this analysis to participants who had both their initial and follow-up chest CTs with identical scanning parameters and comparable lung volumes between the two scans to minimize variability in the data. We hypothesized that baseline PRM fSAD is a radiographic precursor to emphysema.
Methods
Study Participants and Design
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CT Protocol and PRM Analysis
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CTadjusted_baseline(x→)=(CTbaseline(x→)+1000HU)VbaselineVfollow−up−1000HU C
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_
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x
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where V represents the total lung volume obtained from a segmentation of the left and right lungs on the CT image. Parametric Response Maps were then generated for the baseline and follow-up time points by Imbio LLC (Minneapolis, Minnesota, USA) ( ). Briefly, all voxels < −950 HU on the inspiration scan were classified as PRM EMPH , voxels ≥ −950 HU on the inspiration scan and < −856 HU on the expiration scan were classified as PRM fSAD , and voxels ≥ −950 HU on the inspiration scan and ≥ −856 HU on the expiration scan were classified as PRM NORM .
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Statistical Analyses
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Results
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Table 1
Baseline Characteristics of Study Participants
GOLD 0 ( n = 419) GOLD 1–4 ( n = 306)p value Demographics Age 57.4 (8.5) 63.1 (8.3) <0.001 Female (%) 219 (52.3%) 153 (50.0%) 0.55 African-American (%) 153 (36.5%) 86 (28.1%) 0.02 Smoking Exposure Smoking history (pack-years) 36.2 (19.4) 47.2 (21.8) <0.001 Current smoking (%) 210 (50.1%) 133 (43.5%) 0.07 Post-bronchodilator Spirometry FEV 1 (L) 2.84 (0.68) 1.72 (0.73) <0.001 FEV 1 % predicted 97.7 (11.1) 60.8 (21.8) <0.001 FVC (L) 3.62 (0.88) 3.05 (0.95) <0.001 FVC% predicted 96.5 (11.6) 82.5 (19.2) <0.001 FEV 1 /FVC 0.79 (0.05) 0.55 (0.11) <0.001 Markers of Respiratory Health mMRC score 0.7 (1.2) 1.6 (1.4) <0.001 Total SGRQ score 14.8 (16.2) 31.3 (21.3) <0.001 6-minute walking distance (m) 467.0 (109.4) 400.8 (118.0) <0.001 Exacerbation frequency in past 12 months 0.2 (0.5) 0.5 (0.9) <0.001
Data are expressed as mean (standard deviation) except when stated and represent parameters from the baseline visit. The mMRC score ranges from 0 to 4 with higher scores indicating worse dyspnea. The SGRQ score ranges from 0 to 100 with higher scores indicating a higher respiratory burden and worse quality of life.
FEV 1 , forced expiratory volume in the first second; FVC, forced vital capacity; mMRC, modified medical research council; SGRQ, St. George’s Respiratory Questionnaire.
Table 2
Spirometry and PRM Chest CT Metrics for GOLD 1–4 Participants at the Baseline and Follow-up Visits
ALL ( n = 306) Nonprogressors ( n = 153) Progressors ( n = 153) Spirometry Baseline Follow-up Baseline Follow-up Baseline Follow-up FEV 1 (L) 1.72 (0.73) 1.56 (0.73) 1.82 (0.70) 1.71 (0.72) 1.62 (0.75) 1.42 (0.71) FEV 1 % predicted 60.8 (21.8) 59.4 (23.7) 64.3 (20.8) 65.0 (22.8) 57.4 (22.3) 53.9 (23.3) FEV 1 /FVC 0.55 (0.11) 0.55 (0.14) 0.59 (0.10) 0.59 (0.13) 0.52 (0.11) 0.50 (0.14) Chest CT Metrics Baseline Follow-up Baseline Follow-up Baseline Follow-up % PRM fSAD 24.6 (13.5) 25.2 (12.6) 20.7 (12.4) 20.1 (12.0) 28.4 (13.5) 30.3 (11.0) % PRM EMPH 9.6 (10.6) 11.2 (11.7) 6.3 (8.6) 5.9 (7.9) 12.8 (11.4) 16.3 (12.4)
Data are expressed as mean (standard deviation).
FEV 1 , forced expiratory volume in the first second; FVC, forced vital capacity; % PRM fSAD and % PRM EMPH , total lung percent of functional small airway disease and emphysema on chest CT Parametric Response Mapping analysis.
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![Figure 1, Five-year change of chest CT Parametric Response Mapping metrics in GOLD 0 and GOLD 1–4 progressors. The center of each circle represents the mean coordinates (% PRM EMPH and % PRM fSAD ) for each type of progression (to fSAD [A], emphysema [B], or both [C]) at the baseline and follow-up visits (identified by the direction of the arrows ). The area of each circle is proportional to the number of subjects with a given type of progression (A, B, or C) within their GOLD category (0 or 1–4). CT, computed tomography; GOLD, Global initiative for chronic Obstructive Lung Disease. (Color version of figure is available online.)](https://storage.googleapis.com/dl.dentistrykey.com/clinical/ReprintofVoxelWiseLongitudinalParametricResponseMappingAnalysisofChestComputedTomographyinSmokers/0_1s20S1076633219300698.jpg)
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Table 3
Model Showing the Associations Between Clinical and Radiological Variables at Baseline and the 5-year Change in Total Lung PRM EMPH for All GOLD 1–4 Participants
Estimate 95% CI_p_ value Age, per 1-year −0.007 −0.05; 0.04 0.78 Female 0.16 −0.52; 0.84 0.64 African-American 0.35 −0.45; 1.14 0.40 Smoking history, per 1 pack-year 0.02 −0.0007; 0.03 0.06 Current smoking 1.42 0.61; 2.22 0.0007 Postbronchodilator FEV 1 % predicted, per 1% −0.02 −0.06; 0.03 0.42 Postbronchodilator FVC % predicted, per 1% 0.03 −0.01; 0.07 0.19 Bronchodilator response −0.23 −0.96; 0.50 0.53 Baseline PRM fSAD , per 1% 0.05 0.01; 0.09 0.009 Baseline PRM EMPH < 10%, per 1% 0.19 0.05; 0.33 0.007 Baseline PRM EMPH ≥ 10%, per 1% −0.23 −0.40; −0.06 0.007
The model was also adjusted for scanner type. Spline term included at baseline PRM EMPH ≥10%.
FEV 1 , forced expiratory volume in the first second; FVC, forced vital capacity; PRM fSAD and PRM EMPH , total lung percent of functional small airway disease and emphysema on chest CT Parametric Response Mapping analysis.
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DISCUSSION
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Acknowledgments
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