Disease Severity Dependence of the Longitudinal Association Between CT Lung Density and Lung Function in Smokers

doi:10.1016/j.chest.2017.10.012

Chest

Volume 153, Issue 3, March 2018, Pages 638-645

https://doi.org/10.1016/j.chest.2017.10.012 Get rights and content

Background

In smokers, the lung parenchyma is characterized by inflammation and emphysema, processes that can result in local gain and loss of lung tissue. CT measures of lung density might reflect lung tissue changes; however, longitudinal data regarding the effects of CT lung tissue on FEV₁ in smokers with and without COPD are scarce.

Methods

The 15th percentile of CT lung density was obtained from the scans of 3,390 smokers who completed baseline and 5-year follow-up of the Genetic Epidemiology of COPD (COPDGene) study visits. The longitudinal relationship between total lung capacity-adjusted lung density (TLC-PD15) and FEV₁ was assessed by using multivariable mixed models. Separate models were performed in smokers at risk, smokers with preserved ratio and impaired spirometry (PRISm), and smokers with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system.

Results

The direction of the relationship between lung density and lung function was GOLD stage dependent. In smokers with PRISm, a 1-g/L decrease in TLC-PD15 was associated with an increase of 2.8 mL FEV₁ (P = .02). In contrast, among smokers with GOLD III to IV COPD, a 1-g/L decrease in TLC-PD15 was associated with a decrease of 4.1 mL FEV₁ (P = .002).

Conclusions

A decline in TLC-PD15 was associated with an increase or decrease in FEV₁ depending on disease severity. The associations are GOLD stage specific, and their presence might influence the interpretation of future studies that use CT lung density as an intermediate study end point for a decline in lung function.

Trial Registry

ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Section snippets

Study Population

The COPDGene study has been described in detail previously¹⁶ and is expanded on in e-Appendix 1. At baseline, subjects underwent detailed characterization, including the following: volumetric inspiratory CT scans of the chest; questionnaires; and spirometric measures of lung function. COPDGene subjects were asked to return for a 5-year interval visit to repeat the characterization performed at baseline. We used the first 5,000 dataset of subjects who completed the second visit for this analysis.

Results

Complete longitudinal CT, clinical, and spirometric data were available on 3,390 of the 5,000 subjects (Fig 1). Participants with missing data were more likely to be African American (26% vs 33%) and have lower FEV₁ (2.35 vs. 2.25 L; P = .0002), with no differences in age, pack-years, or sex and smoking status proportions (P > .05). The details of the remaining cohort are provided in Table 1.

Discussion

We analyzed the clinical and imaging data from > 3,300 subjects in the COPDGene study, one of the largest cohorts of smokers with a full range of disease. The data suggest two important features that must be considered when using CT imaging as an intermediate study end point for smokers. The first is that the progression of parenchymal disease on CT scan is not consistent across GOLD stages and in fact may be characterized by an increase or decrease in low attenuating tissue over a limited

Acknowledgments

Author contributions: A. A. D., M. S., and G. R. W. served as guarantors and take full responsibility for the content of the manuscript, including the data analysis. A. A. D., M. S., H. O. C., J. C. R., R. S. J. E., D. L., E. M. V. R., I. O. R., G. M. H., R. K. P., H. H., A. Y., G. L. K., J. E. H., E. K. S., J. C., and G. R. W. were responsible for the conception and design of this study and creation, revision, and final approval of the manuscript. A. A. D., M. S., E. K. S., and G. R. W.

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The Dlco and K_CO decline was weakly associated with FEV₁ and greater in GOLD stage 3 or higher than in GOLD stages 1 and 2. Furthermore, moderate or more severe CLE, but not present PSE, was associated with steeper declines in Dlco for GOLD stages 1 and 3 or higher and K_CO for all GOLD stages independent of age, sex, height, and smoking history. The moderate or more severe CLE, but not present PSE, was associated with additional FEV₁ decline and higher 10-year mortality among patients with GOLD stage 3 or higher.
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Preserved Ratio Impaired Spirometry in Relationship to Cardiovascular Outcomes: A Large Prospective Cohort Study
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Preserved ratio impaired spirometry (PRISm) findings are a heterogeneous condition characterized by a normal FEV₁ to FVC ratio with underlying impairment of pulmonary function. Data relating to the association of baseline and trajectories of PRISm findings with diverse cardiovascular outcomes are sparse.
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In the UK Biobank cohort study, we included participants free of cardiovascular disease (CVD) with spirometry (FEV₁ and FVC values) at baseline (2006-2010). Participants with baseline spirometry and follow-up spirometry (2014-2020) were included in the lung function trajectory analysis. Cox proportional hazards multivariate regression was performed to evaluate the outcomes of major adverse cardiovascular events (MACEs), incident myocardial infarction (MI), stroke, heart failure (HF), and CVD mortality in association with lung function.
For baseline analysis (329,954 participants), the multivariate adjusted hazard ratios (HRs) for participants had PRISm findings (vs normal spirometry findings) were 1.26 (95% CI, 1.17-1.35) for MACE, 1.12 (95% CI, 1.01-1.25) for MI, 1.88 (95% CI, 1.72-2.05) for HF, 1.26 (95% CI, 1.13-1.40) for stroke, and 1.55 (95% CI, 1.37-1.76) for CVD mortality, respectively. A total of 22,781 participants underwent follow-up spirometry after an average of 8.9 years. Trajectory analysis showed that persistent PRISm findings (HR, 1.96; 95% CI, 1.24-3.09) and airflow obstruction (HR, 1.43; 95% CI, 1.00-2.04) was associated with a higher incidence of MACE vs consistently normal lung function. Compared with persistent PRISm findings, changing from PRISm to normal spirometry findings was associated with a lower incidence of MACE (HR, 0.42; 95% CI, 0.19-0.99).
Individuals with baseline or persistent PRISm findings were at a higher risk of diverse cardiovascular outcomes even after adjusting for a wide range of confounding factors. However, individuals who transitioned from PRISm to normal findings showed a similar cardiovascular risk as those with normal lung function.
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Citation Excerpt :
COPDGene is a prospective cohort of more than 10,300 non-Hispanic White and Black ever-smokers with at least a 10-pack-year smoking history, aged 45 to 80 years, without prior bronchiectasis or ILD, from 21 study centers in the United States.14 At baseline visit 1 (2006-2011) and visit 2 (2013-2017) approximately 5 years later, participants underwent collection of inspiratory and expiratory chest CT scans, pre- and postbronchodilator spirometric testing, 6-min walk distance (6MWD) measurements, questionnaires, and genotyping of the MUC5B polymorphism (rs35705950).8,17 Participants with a postbronchodilator FEV1 ≥ 80% predicted and FEV1-to-FVC ratio ≥ 0.7 were defined as in GOLD stage 0, and those with a postbronchodilator FEV1 ≤ 80% predicted and a FEV1-to-FVC ratio ≥ 0.7 were defined as having PRISm.
The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized.
What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression?
Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the longitudinal associations between progression and FVC and 6-min walk distance, and Cox regression models for the association with mortality.
Age at enrollment, female sex, current smoking status, and the MUC5B minor allele were associated with quantitative interstitial abnormality progression. Each percent annual increase in quantitative interstitial abnormalities was associated with annual declines in FVC (COPDGene: 8.5 mL/y; 95% CI, 4.7-12.4 mL/y; P < .001; PLuSS: 9.5 mL/y; 95% CI, 3.7-15.4 mL/y; P = .001) and 6-min walk distance, and increased mortality (COPDGene: hazard ratio, 1.69; 95% CI, 1.34-2.12; P < .001; PLuSS: hazard ratio, 1.28; 95% CI, 1.10-1.49; P = .001).
The objective, longitudinal measurement of quantitative interstitial abnormalities may help identify people at greatest risk for adverse events and most likely to benefit from early intervention.
CT Imaging-Based Low-Attenuation Super Clusters in Three Dimensions and the Progression of Emphysema
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Distributions of low-attenuation areas in two-dimensional (2-D) CT lung slices are used to quantify parenchymal destruction in patients with COPD. However, these segmental approaches are limited and may not reflect the true three-dimensional (3-D) tissue processes that drive emphysematous changes in the lung. The goal of this study was to instead evaluate distributions of 3-D low-attenuation volumes, which we hypothesized would follow a power law distribution and provide a more complete assessment of the mechanisms underlying disease progression.
CT scans and pulmonary function test results were acquired from an observational database for N = 12 patients with COPD and N = 12 control patients. The data set included baseline and two annual follow-up evaluations in patients with COPD. Three-dimensional representations of the lungs were reconstructed from 2-D axial CT slices, with low-attenuation volumes identified as contiguous voxels < –960 Hounsfield units.
Low-attenuation sizes generally followed a power law distribution, with the exception of large, individual outliers termed “super clusters,” which deviated from the expected distribution. Super cluster volume was correlated with disease severity (% total low attenuation, ρ = 0.950) and clinical measures of lung function including FEV₁ (ρ = –0.849) and diffusing capacity of the lung for carbon monoxide Dlco (ρ = –0.874). To interpret these results, we developed a personalized computational model of super cluster emergence. Simulations indicated disease progression was more likely to occur near existing emphysematous regions, giving rise to a biomechanical, force-induced mechanism of super cluster growth.
Low-attenuation super clusters are defining, quantitative features of parenchymal destruction that dominate disease progression, particularly in advanced COPD.
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: Drs Diaz and Strand contributed equally to this work.

: FUNDING/SUPPORT: This work was supported by National Institutes of Health grants: The Genetic Epidemiology of COPD (COPDGene) study [Grants R01HL089897 and R01HL089856]; Dr Diaz [Grant K01HL118714] and the Brigham and Women’s Hospital Minority Faculty Career Development Award; Dr San José Estépar [Grant R01 HL116473]; and Dr Washko [Grants R01 HL116473 and R01 HL107246].

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Chest

Original Research: COPDDisease Severity Dependence of the Longitudinal Association Between CT Lung Density and Lung Function in Smokers

Background

Methods

Results

Conclusions

Trial Registry

Section snippets

Study Population

Results

Discussion

Acknowledgments

Lancet

J Allergy Clin Immunol

Lancet

Respir Med

Lancet Respir Med

Chest

Acad Radiol

Chest

Comparison of computed density and microscopic morphometry in pulmonary emphysema

Am J Respir Crit Care Med

Using pulmonary imaging to move chronic obstructive pulmonary disease beyond FEV1

Am J Respir Crit Care Med

Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns

Am J Respir Crit Care Med

Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers

Am J Respir Crit Care Med

Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function

Am J Respir Crit Care Med

Original Research: COPD
Disease Severity Dependence of the Longitudinal Association Between CT Lung Density and Lung Function in Smokers