Advertisement

Diffusing Capacity, the Too Often Ignored Lung Function Test in COPD

      FOR RELATED ARTICLE, SEE PAGE 481
      Diffusing capacity of the lungs for carbon monoxide (Dlco), a complex test that provides a quantitative measure of the effective alveolar-capillary surface area available for gas transfer in the lungs, has been referred to as a “window on the pulmonary microcirculation.”
      • Hughes J.M.B.
      The single breath transfer factor (Tl,co) and the transfer coefficient (Kco): a window onto the pulmonary microcirculation.
      In 1957, Roughton and Forster
      • Roughton F.J.W.
      • Forster R.E.
      Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries.
      simplified our physiologic understanding of this process, describing two conductance properties in series: the membrane component (Dm) describing the transfer of CO molecules across the alveolar-capillary membrane and the binding of CO molecules with hemoglobin (θ) multiplied by the pulmonary capillary blood volume (Vc). Dlco, along with spirometry and arterial blood gas measurement, are core pulmonary function tests used to monitor patients with lung disease. All require close adherence to test standards, although this is particularly important for Dlco to control for the sources of technical, biological, and environmental factors that can contribute to variability.
      Although spirometry is the most common pulmonary function test in COPD, Dlco is useful in differentiating asthma from COPD. More precisely, Dlco is useful in distinguishing patients with emphysema from those with predominantly airway disease (asthma or chronic bronchitis).
      • Knudson R.J.
      • Kaltenborn W.T.
      • Burrows B.
      Single breath carbon monoxide transfer factor in different forms of chronic airflow obstruction in a general population sample.
      Dlco also adds to the predictive power of spirometry and CT scan-based emphysema score for predicting increased symptoms, lower quality of life, decreased exercise performance, and severe exacerbations in patients with COPD.
      • Balasubramanian A.
      • MacIntyre N.R.
      • Henderson R.J.
      • et al.
      Diffusing capacity of carbon monoxide in assessment of COPD.
      A disproportionately reduced Dlco compared with FEV1 suggests COPD with “pulmonary vascular phenotype”
      • Kovacs G.
      • Agusti A.
      • Barberà J.A.
      • et al.
      Pulmonary vascular involvement in chronic obstructive pulmonary disease: is there a pulmonary vascular phenotype?.
      or combined pulmonary fibrosis and emphysema,
      • Jankowich M.D.
      • Rounds S.I.S.
      Combined pulmonary fibrosis and emphysema syndrome: a review.
      disease processes with increased mortality.
      In this issue of CHEST, Casanova et al
      • Casanova C.
      • Gonzalez-Dávila E.
      • Martínez-Gonzalez C.
      • et al.
      Natural course of the diffusing capacity of the lungs for carbon monoxide in COPD: importance of sex.
      describe the natural course of Dlco in 602 smokers, 84% with COPD, over a 5-year time period. The important findings are that patients with COPD have an increased yearly decline in percent predicted Dlco compared with smokers without airway obstruction. However, only 16% of patients with COPD, vs 4.3% of smokers without COPD, were found to have a significant yearly decline in the slope of percent predicted Dlco. Women with COPD had lower Dlco values, despite having higher spirometry values, and, importantly, also had a steeper annual decline in percent predicted Dlco.
      These findings add to our understanding of COPD progression but also raise other questions. A rapidly declining Dlco in COPD suggests one of two pathophysiologic processes is occurring: progression of emphysema or pulmonary vascular derangements. The lower Dlco and steeper decline in Dlco in women despite better spirometric values reported by Casanova et al
      • Casanova C.
      • Gonzalez-Dávila E.
      • Martínez-Gonzalez C.
      • et al.
      Natural course of the diffusing capacity of the lungs for carbon monoxide in COPD: importance of sex.
      suggest one or both of these processes occurs with more severity in women. In light of other studies showing women have less emphysema than men when assessed by CT imaging, this suggests that pulmonary vascular changes
      • Peinado V.I.
      • Barberà J.A.
      • Abate P.
      • et al.
      Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.
      or small conducting airway narrowing and destruction, described as “pruning,”
      • McDonough J.E.
      • Yuan R.
      • Suzuki M.
      • et al.
      Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.
      may be the predominant cause of the lower Dlco in women. The lower Dlco and more rapid decline in Dlco in women may help explain why women with COPD report more dyspnea and worse health status, both pointed out in this study.
      Features suggesting a pulmonary vascular phenotype have been suggested. In COPD, these include mildly to moderately impaired spirometry (FEV1 > 60% predicted) and a disproportionate, severely decreased Dlco (“low Dlco in relation to obstructive changes”), absence of or only modest airway/parenchymal abnormalities, moderate-to-severe pulmonary hypertension by right heart catheterization, and a circulatory limitation (as opposed to a ventilatory limitation) to exercise on cardiopulmonary exercise testing.
      • Nathan S.D.
      • Barbera J.A.
      • Gaine S.P.
      • et al.
      Pulmonary hypertension in chronic lung disease and hypoxia.
      Female sex is a known risk factor for group 1 pulmonary arterial hypertension (PAH), and much attention is currently focused on this as bone morphogenetic protein signaling and estrogen pathways may act by synergistic mechanisms to increase the risk of PAH in women.
      • Cirulis M.M.
      • Dodson M.W.
      • Brown L.M.
      • Brown S.M.
      • Lahm T.
      • Elliott G.
      At the X-roads of sex and genetics in pulmonary arterial hypertension.
      Going forward, the roles of sex and hormonal factors appear to be an important area to better understand the differences seen in gas transfer measurements in women with COPD. Interestingly, this study by Casanova et al
      • Casanova C.
      • Gonzalez-Dávila E.
      • Martínez-Gonzalez C.
      • et al.
      Natural course of the diffusing capacity of the lungs for carbon monoxide in COPD: importance of sex.
      using Dlco reinforces the conclusion drawn by Balasubramanian et al,
      • Balasubramanian A.
      • MacIntyre N.R.
      • Henderson R.J.
      • et al.
      Diffusing capacity of carbon monoxide in assessment of COPD.
      that the interactions between vascular and pulmonary physiology in COPD represent an area that requires more investigation.
      Overall, this study suggests that COPD progression is relatively slow: an average of 3 to 4 years was required to detect a significant change. This suggests that Dlco testing could be performed every 3 to 4 years as opposed to yearly or more frequently in COPD to document rapid decliners. Furthermore, as Casanova et al
      • Casanova C.
      • Gonzalez-Dávila E.
      • Martínez-Gonzalez C.
      • et al.
      Natural course of the diffusing capacity of the lungs for carbon monoxide in COPD: importance of sex.
      note, future studies using Dlco measurements in COPD should take this slow decline into account when designing trials and analysis.
      Dlco measurements are clinically useful in caring for patients with COPD. There is mounting evidence of sex-related differences in COPD risk, progression, and outcomes, which remains an understudied women’s health issue.
      • Jenkins C.R.
      • Chapman K.R.
      • Donohue J.F.
      • Roche N.
      • Tsiligianni I.
      • Han M.K.
      Improving the management of COPD in women.
      Our current inability to explain the differences between men and women with COPD indicates that the observations described by Casanova et al
      • Casanova C.
      • Gonzalez-Dávila E.
      • Martínez-Gonzalez C.
      • et al.
      Natural course of the diffusing capacity of the lungs for carbon monoxide in COPD: importance of sex.
      deserve further investigation to improve care for all individuals with COPD.

      References

        • Hughes J.M.B.
        The single breath transfer factor (Tl,co) and the transfer coefficient (Kco): a window onto the pulmonary microcirculation.
        Clin Physiol Funct Imaging. 2003; 23: 63-71
        • Roughton F.J.W.
        • Forster R.E.
        Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries.
        J Appl Physiol. 1957; 11: 290-302
        • Knudson R.J.
        • Kaltenborn W.T.
        • Burrows B.
        Single breath carbon monoxide transfer factor in different forms of chronic airflow obstruction in a general population sample.
        Thorax. 1990; 45: 514-519
        • Balasubramanian A.
        • MacIntyre N.R.
        • Henderson R.J.
        • et al.
        Diffusing capacity of carbon monoxide in assessment of COPD.
        Chest. 2019; 156: 1111-1119
        • Kovacs G.
        • Agusti A.
        • Barberà J.A.
        • et al.
        Pulmonary vascular involvement in chronic obstructive pulmonary disease: is there a pulmonary vascular phenotype?.
        Am J Respir Crit Care Med. 2018; 198: 1000-1011
        • Jankowich M.D.
        • Rounds S.I.S.
        Combined pulmonary fibrosis and emphysema syndrome: a review.
        Chest. 2012; 141: 222-231
        • Casanova C.
        • Gonzalez-Dávila E.
        • Martínez-Gonzalez C.
        • et al.
        Natural course of the diffusing capacity of the lungs for carbon monoxide in COPD: importance of sex.
        Chest. 2021; 160: 481-490
        • Peinado V.I.
        • Barberà J.A.
        • Abate P.
        • et al.
        Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 1999; 159: 1605-1611
        • McDonough J.E.
        • Yuan R.
        • Suzuki M.
        • et al.
        Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.
        N Engl J Med. 2011; 365: 1567-1575
        • Nathan S.D.
        • Barbera J.A.
        • Gaine S.P.
        • et al.
        Pulmonary hypertension in chronic lung disease and hypoxia.
        Eur Respir J. 2019; 53: 1801914
        • Cirulis M.M.
        • Dodson M.W.
        • Brown L.M.
        • Brown S.M.
        • Lahm T.
        • Elliott G.
        At the X-roads of sex and genetics in pulmonary arterial hypertension.
        Genes. 2020; 11: 1371
        • Jenkins C.R.
        • Chapman K.R.
        • Donohue J.F.
        • Roche N.
        • Tsiligianni I.
        • Han M.K.
        Improving the management of COPD in women.
        Chest. 2017; 151: 686-696

      Linked Article