- Letter to the Editor
- Open Access
Relationship between diffusion capacity and small airway abnormality in COPDGene
Respiratory Research volume 20, Article number: 269 (2019)
Impaired single breath carbon monoxide diffusing capacity (DLCO) is associated with emphysema. Small airways disease (SAD) may be a precursor lesion to emphysema, but the relationship between SAD and DLCO is undescribed. We hypothesized that in mild COPD, functional SAD (fSAD) defined by computed tomography (CT) and Parametric Response Mapping methodology would correlate with impaired DLCO. Using data from ever-smokers in the COPDGene cohort, we established that fSAD correlated significantly with lower DLCO among both non-obstructed and GOLD 1–2 subjects. The relationship between DLCO with CT-defined emphysema was present in all GOLD stages, but most prominent in severe disease.
NCT00608764. Registry: COPDGene. Registered 06 February 2008, retrospectively registered.
The importance of small airways disease (SAD) in COPD pathogenesis was first described by Hogg et al. in the 1960s, who determined that peripheral resistance contributes minimally to total airway resistance in healthy lungs but significantly in emphysematous lungs . Recent research using advanced computed tomography (CT) has further suggested that a CT metric for small airway disease (SAD) radiographically precedes emphysema development and is associated with subsequent FEV1 decline [2, 3].
Diffusing capacity of the lung (DLCO) is a commonly tested measurement in pulmonary function studies, indirectly measuring degree of gas transfer from alveoli to pulmonary capillary blood, with results depending on the lung’s structural and functional properties. Emphysema irreversibly destroys alveoli, leading to gas exchange impairment and manifesting as an inverse relationship between emphysema severity and DLCO . We hypothesized that CT defined SAD among COPD subjects with mild disease (GOLD 1–2) may detect lung regions in transition from bronchiolar pathology to emphysema, and hence, may be associated with diffusion capacity impairment.
We analyzed data from the five-year follow-up visit of the COPDGene cohort in individuals (n = 1846) with ≥10 pack-years smoking history and GOLD spirometric grades 0–4 for whom DLCO and CT imaging data were available and obtained on the same day. GOLD 0, although no longer used in the GOLD strategic document, includes non-obstructed smokers (post-bronchodilator FEV1/FVC > 0.7). COPDGene is a longitudinal, observational, and multicenter study investigating underlying genetic determinants of COPD (Clinicaltrials.gov identifier NCT00608764). DLCO was measured with EasyOne Pro (serial number 500633, ndd Medizintechnik AG, Zurich, Switzerland). Percent predicted values and z-scores were calculated from raw values using Global Lung Function Initiative (GLI) equations. We processed inspiratory and expiratory CT images by parametric response mapping (PRM), a novel CT biomarker technique, using Imbio Lung Density Analysis dynamic image registration software (Minneapolis, MN) to quantify areas of emphysema (PRMEmph) and areas of non-emphysematous gas trapping recently determined to be SAD (PRMfSAD) . Multivariable regression models for DLCO GLI z-score were created to determine the relative contribution of PRMEmph and PRMfSAD, additionally adjusted for age, sex, and current smoking.
Participant mean age at time of measurement was 67.0 years. With increasing GOLD stage, DLCO % predicted fell and z-scores became more negative, while PRMEmph and PRMfSAD rose. These characteristics, as well as other subject characteristics, are shown in Table 1.
In a multivariable regression model examining non-obstructed ever-smokers, PRMfSAD (β = − 0.03, p < 0.001) and PRMEmph (β = − 0.04, p = 0.03) were associated with lower DLCO GLI z-score. For clinical interpretation, on average a non-obstructed individual with 10% higher PRMfSAD would be predicted to have 3.1% lower DLCO % predicted. In GOLD 1–2, both PRMfSAD (β = − 0.02, p = 0.004) and PRMEmph (β = −.10, p < 0.008) were associated with lower DLCO GLI z-score. Among GOLD 3–4, PRMEmph (β = − 0.11, p < 0.001) but not PRMfSAD (p = 0.69) was associated with lower GLI z-score.
Our analysis of a sizeable group of current and former smokers indicate that in those without airflow obstruction and in individuals with mild to moderate COPD, small airways disease defined by PRM is associated with significant gas exchange abnormalities. These data build on and extend recent work to elucidate the nature of small airway abnormality in COPD. The PRMfSAD metric has been associated with more rapid lung function decline, even among individuals with emphysema . Using longitudinal image registration, we previously showed that voxels identified as PRMfSAD radiographically precede development of CT-determined emphysema in those same voxels . Importantly, we recently demonstrated with severe COPD human lung tissue that PRMfSAD metric corresponds to pathologic abnormality, including decreased circularity, decreased luminal area, and complete obstruction of terminal bronchioles (TBr), whereas PRMEmph is significantly associated with decreased alveolar surface area .
However, the pathology identified by PRMfSAD in milder disease is unknown. Given the totality of data generated to date, PRMfSAD is also likely associated with TBr pathology in mild COPD, but the extent to which it may also identify early alveolar destruction must be determined.
The association we show here between PRMfSAD and reduced DLCO suggests that the fSAD metric may detect lung beginning to transition from bronchiolar pathology to emphysema.
Support for this possibility comes from McDonough et al., who used micro-CT to analyze lung tissue samples in severe COPD. By identifying significantly reduced TBr numbers in areas of lung without visible emphysema evidence, they inferred that narrowing and loss of TBr precedes emphysema . However, a linear relationship between loss of TBr and increase in mean linear intercept (a measure of mean free distance in the air spaces) was seen. Most recently, Koo et al. examined lung tissue from GOLD 1–2 stage disease and again found significant reductions in number of TBr and transitional bronchioles in lung areas without visible emphysema . Collectively, these results support SAD as one precursor of emphysema.
DLCO is well-established to correlate with CT-determined emphysema , but it may also be decreased in mild COPD, where emphysema is not detectable by CT imaging. Active smokers with normal spirometry but low DLCO had increased rate of progression to GOLD-defined COPD, compared to smokers with normal spirometry and normal DLCO, implying that isolated decreased DLCO is a risk factor for airflow obstruction in otherwise healthy subjects . Ex-smokers with normal CTs and no airflow obstruction but with low DLCO had significantly worse symptoms and exercise capacity as well as greater regional lung destruction, as measured by hyperpolarized 3He MRI apparent diffusion coefficients . In 10 patients with severe SAD, defined by severe expiratory airflow limitation with mild CT-detected emphysema, Gelb et al. found DLCO reductions; however, they proposed that this was possibly due to uneven gas sampling from lung units with differing expiratory time constants, a function of SAD rather than lung parenchymal destruction .
Our current analysis of ever-smokers without obstruction and with GOLD 1–2 COPD showed that PRMfSAD correlates with low DLCO, suggesting PRMfSAD might detect airways transitioning to early emphysema with resulting impaired gas exchange. Although COPD is a heterogonous disease, it is possible that a significant portion of small airways disease patients will progress to emphysema. Therefore, in addition to already describing correlations between tissue pathology and PRMfSAD in severe disease, similar studies in milder disease are also needed to confirm the pathology type identified in this population, who may be more amenable to therapeutic intervention that may halt progression to emphysema.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Diffusing capacity of the lung
Functional small airways disease
Global Lung Function Initiative
Parametric response mapping
- PRMEmph :
Emphysema as determined by PRM
- PRMfSAD :
Small airways disease as determined by PRM
Small airways disease
Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med. 1968;278:1355–60.
McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, Wright AC, Gefter WB, Litzky L, Coxson HO, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365:1567–75.
Koo HK, Vasilescu DM, Booth S, Hsieh A, Katsamenis OL, Fishbane N, Elliott WM, Kirby M, Lackie P, Sinclair I, et al. Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study. Lancet Respir Med. 2018;6:591–602.
D'Anna SE, Asnaghi R, Caramori G, Appendini L, Rizzo M, Cavallaro C, Marino G, Cappello F, Balbi B, Di Stefano A. High-resolution computed tomography quantitation of emphysema is correlated with selected lung function values in stable COPD. Respiration. 2012;83:383–90.
Vasilescu DM, Martinez FJ, Marchetti N, Galban CJ, Hatt C, Meldrum CA, Dass C, Tanabe N, Reddy RM, Lagstein A, et al. Non-invasive imaging biomarker identifies small airway damage in severe COPD. Am J Respir Crit Care Med. 2019;200:575–81.
Bhatt SP, Soler X, Wang X, Murray S, Anzueto AR, Beaty TH, Boriek AM, Casaburi R, Criner GJ, Diaz AA, et al. Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2016;194:178–84.
Labaki WW, Gu T, Murray S, Hatt CR, Galban CJ, Ross BD, Martinez CH, Curtis JL, Hoffman EA, Pompe E, et al. Voxel-wise longitudinal parametric response mapping analysis of chest computed tomography in smokers. Acad Radiol. 2019;26:306–12.
Harvey B-G, Strulovici-Barel Y, Kaner RJ, Sanders A, Vincent TL, Mezey JG, Crystal RG. Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity. Eur Respir J. 2015;46:1589–97.
Kirby M, Owrangi A, Svenningsen S, Wheatley A, Coxson HO, Paterson NAM, McCormack DG, Parraga G. On the role of abnormal DLCO in ex-smokers without airflow limitation: symptoms, exercise capacity and hyperpolarised helium-3 MRI. Thorax. 2013;68:752–9.
Gelb AF, Zamel N, Hogg JC, Müller NL, Scheiin MJ. Pseudophysiologic emphysema resulting from severe small-airways disease. Am J Respir Crit Care Med. 1998;158:815–9.
This work was supported by NHLBI U01 HL089897 and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sunovion. Dr. Han is supported by NHLBI K24 HL138188. Dr. Curtis is supported by I01 CX000911 from the Department of Veterans Affairs.
Ethics approval and consent to participate
This research letter presents an analysis of the COPDGene study registered on Clinicaltrials.gov (NCT00608764). The protocol was reviewed and approved by the Institutional Review Boards for each participating center (National Jewish Health, HS-1883a; Brigham and Women’s Hospital, 2007-P-000554/2; Baylor College of Medicine, H-22209; Michael E. DeBakey VAMC, H− 22202; Columbia University Medical Center, IRB-AAAC9324; Duke University Medical Center, Pro00004464; Johns Hopkins University, NA_00011524; Los Angeles Biomedical Research Institute, 12756–01; Morehouse School of Medicine, 07–1029; Temple University, 11369; University of Alabama at Birmingham, FO70712014; University of California, San Diego, 070876; University of Iowa, 200710717; Ann Arbor VA, PCC 2008–110732; University of Minnesota, 0801 M24949; University of Pittsburgh, RO07120059; University of Texas Health Sciences Center at San Antonio, HSC20070644H; Health Partners Research Foundation, 07–127; University of Michigan, HUM00014973; Minneapolis VA Medical Center, 4128-A; Fallon Clinic, 1143).
Consent for publication
RNC, EAK, NM, RC, WWL – none.
CRH – An employee of and has stock options in Imbio LLC, which has licensed the PRM technology for use as FDA-approved commercial software.
DAL - Reports grants from NHLBI and has a pending patent entitled Systems and Methods for Classifying Severity of COPD.
CJG – Is co-inventor of PRM, which is licensed to Imbio by the University of Michigan.
MM – Reports other support from UpToDate.
BM – Reports funding from the NHLBI for the COPDGene study; grants and medical advisory boards from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Sunovian; personal fees for DSMB from Spiration and Shire/Baxalta; CME personal fees from WebMD, National Jewish.
Health, American College of Chest Physicians, Projects in Knowledge, Hybrid Communications, SPIRE Learning, Ultimate Medical Academy, Catamount Medical, Eastern Pulmonary Society, Catamount Medical Communications Medscape, Eastern VA Medical Center, Academy Continued Healthcare Learning, and Mt. Sinai Medical Center; royalties from Up-To-Date; medical advisory boards from Novartis, Phillips, Third Pole, Science 24/7, and Vernoa; and grants from Pearl.
FJM - Receives personal fees and non-financial support from American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, ConCert, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications Puerto Rican Respiratory Society, Chiesi, Sunovion, Theravance, Physicians Education Resource, Canadian Respiratory Network, Teva, and Dartmouth. Receives non-financial support from ProterrixBio, Gilead, Nitto, Potomac, University of Alabama Birmingham, and Zambon. Receives personal fees from Columbia University, Integritas, MD Magazine, Methodist Hospital Brooklyn, New York University, UpToDate, WebMD/MedScape, Western Connecticut Health Network, Patara/Respivant, PlatformIQ, American Thoracic Society, Rockpointe, Rare Disease Healthcare Communications, and France Foundation. He receives grants from the NIH. He also receives other support from Afferent/Merck, Biogen, Veracyte, Prometic, Bayer, Bridge Biotherapeutics, and ProMedior.
JLC - Reports grants from NIH/NHLBI, NIH/NIAID, the Department of Veterans Affairs, and the Department of Defense.
MKH - Reports grants from NIH, personal fees from BI, GSK, AZ, and Mylan. She also receives other support from Novartis and Sunovion.
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Criner, R.N., Hatt, C.R., Galbán, C.J. et al. Relationship between diffusion capacity and small airway abnormality in COPDGene. Respir Res 20, 269 (2019). https://doi.org/10.1186/s12931-019-1237-1
- Diffusing capacity of the lung (DLCO)
- Small airways disease (SAD)
- Chronic obstructive pulmonary disease (COPD)
- Parametric response mapping (PRM)