Diffusing Capacity Is an Independent Predictor of Outcomes in Pulmonary Hypertension Associated With COPD

doi:10.1016/j.chest.2020.02.047

Chest

Volume 158, Issue 2, August 2020, Pages 722-734

Part of this article has been presented at the American Thoracic Society International Conference, May 17-22, 2019, Dallas, TX.

https://doi.org/10.1016/j.chest.2020.02.047 Get rights and content

Background

Patients with COPD who experience pulmonary hypertension (PH) have worse mortality than those with COPD alone. Predictors of poor outcomes in COPD-PH are not well-described. Diffusing capacity of the lung (Dlco) assesses the integrity of the alveolar-capillary interface and thus may be a useful prognostic tool among those with COPD-PH.

Research Question

Using a single center registry, we sought to evaluate Dlco as a predictor of mortality in a cohort of patients with COPD-PH.

Study Design and Methods

This retrospective cohort study analyzed 71 COPD-PH patients from the Johns Hopkins Pulmonary Hypertension Registry with right-sided heart catheterization (RHC)-proven PH and pulmonary function testing data within one year of diagnostic RHC. Transplant-free survival was calculated from index RHC. Adjusted transplant-free survival was modelled using Cox proportional hazard methods; age, pulmonary vascular resistance, FEV₁, oxygen use, and N-terminal pro-brain natriuretic peptide were included as covariates.

Results

Overall unadjusted transplant-free 1-, 3-, and 5-year survivals were 87%, 60%, and 51%, respectively. Survival was associated with reduced Dlco across the observed range of pulmonary artery pressures and pulmonary vascular resistance. Severe Dlco impairment was associated with poorer survival (log-rank χ² 13.07) (P < .001); adjusting for covariates, for every percent predicted decrease in Dlco, mortality rates increased by 4% (hazard ratio, 1.04; 95% CI, 1.01-1.07).

Interpretation

Among patients with COPD-PH, severe gas transfer impairment is associated with higher mortality, even with adjustment for airflow obstruction and hemodynamics, which suggests that Dlco may be a useful prognostic marker in this population. Future studies are needed to further investigate the association between Dlco and morbidity and to determine the utility of Dlco as a biomarker for disease risk and severity in COPD-PH.

Section snippets

Study Population and Design

This retrospective cohort study examined patients with COPD-PH who were enrolled in the Johns Hopkins Pulmonary Hypertension Registry, an Institutional Review Board-approved registry of patients seen at Johns Hopkins University, Baltimore, MD. All patients enrolled in the registry provide written informed consent for data collection.

From January 2000 to January 2018, 95 participants were identified on initial screening for patients enrolled with COPD designated as the primary cause for their

Characteristics of a Patient With COPD-PH

Baseline characteristics for all 71 patients with COPD-PH are described in Table 1. Patients were on average 65 years old, 66% female, with BMI of 28.3 kg/m², and 44 pack-years smoked. Approximately three-quarters of them used supplemental oxygen, and nearly 60% were World Health Organization Functional Classification III/IV at index catheterization. PFT demonstrated moderate-severe obstruction (FEV₁ 52±20%), with severe gas transfer defects (Dlco 43±20%), and severely impaired 6MWD (265±124

Discussion

In a cohort of patients with COPD-PH from a PH tertiary referral center, we have demonstrated that (1) overall prognosis is poor among this population, (2) airflow obstruction does not predict death, and (3) gas transfer is a strong independent predictor of death. Gas transfer was observed to be the only significant predictor of death, after accounting for airflow obstruction and hemodynamics, with a 4% increase in mortality rate for every 1% decrease in Dlco. In the context of increasing

Acknowledgments

Author contributions: S. C. M. contributed to the conception, design of the study, data analysis, interpretation, and preparation of this manuscript and is the guarantor of this paper. A. B. contributed to the conception, design of the study, data analysis, interpretation, and manuscript writing. T. M. K., R. L. D., P. M. H., and M. C. M. contributed to data interpretation and revision of the manuscript. All authors reviewed and approved the manuscript prior to submission for publication.

References (65)

O.A. Minai et al.
Pulmonary hypertension in COPD: epidemiology, significance, and management: pulmonary vascular disease: the global perspective
Chest
(2010)
M. Oswald-Mammosser et al.
Prognostic factors in COPD patients receiving long-term oxygen therapy
Chest
(1995)
O.A. Minai et al.
Clinical characteristics and prediction of pulmonary hypertension in severe emphysema
Respir Med
(2014)
K.H. Andersen et al.
Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease
J Heart Lung Transplant
(2012)
M.K. Han et al.
GOLD 2011 disease severity classification in COPDGene: a prospective cohort study
Lancet Respir Med
(2013)
A. Balasubramanian et al.
Diffusing capacity of carbon monoxide in assessment of chronic obstructive pulmonary disease
Chest
(2019)
S. Chandra et al.
Carbon monoxide diffusing capacity and mortality in pulmonary arterial hypertension
J Heart Lung Transplant
(2010)
M.M. Hoeper et al.
Diffusion capacity and mortality in patients with pulmonary hypertension due to heart failure with preserved ejection fraction
JACC Heart Fail
(2016)
L. Rose et al.
Survival in pulmonary hypertension due to chronic lung disease: influence of low diffusion capacity of the lungs for carbon monoxide
J Heart Lung Transplant
(2019)
K. Hamada et al.
Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis
Chest
(2007)

P. Peduzzi et al.

A simulation study of the number of events per variable in logistic regression analysis

J Clin Epidemiol

(1996)

W. Seeger et al.

Pulmonary hypertension in chronic lung diseases

J Am Coll Cardiol

(2013)

H. Gall et al.

The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups

J Heart Lung Transplant

(2017)

A. Nambu et al.

Relationships between diffusing capacity for carbon monoxide (Dlco), and quantitative computed tomography measurements and visual assessment for chronic obstructive pulmonary disease

Eur J Radiol

(2015)

V.I. Peinado et al.

Pulmonary vascular abnormalities in chronic obstructive pulmonary disease undergoing lung transplant

J Heart Lung Transplant

(2013)

J. Carlsen et al.

Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease

J Heart Lung Transplant

(2013)

V. Bunel et al.

Pulmonary arterial histologic lesions in patients with COPD with severe pulmonary hypertension

Chest

(2019)

R. Andrea et al.

Lung function abnormalities are highly frequent in patients with heart failure and preserved ejection fraction

Heart Lung Circ

(2014)

J.L. Siegel et al.

Pulmonary diffusing capacity in left ventricular dysfunction

Chest

(1990)

S.M. Kawut et al.

New predictors of outcome in idiopathic pulmonary arterial hypertension

Am J Cardiol

(2005)

Z.-C. Jing et al.

Pulmonary function testing in patients with pulmonary arterial hypertension

Respir Med

(2009)

R.L. Benza et al.

Predicting survival in patients with pulmonary arterial hypertension: The REVEAL risk score calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies

Chest

(2019)

G. Thabut et al.

Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation

Chest

(2005)

K.D. Kochanek et al.

Mortality in the United States, 2016

NCHS Data Brief

(2017)

A.G. Wheaton et al.

Employment and activity limitations among adults with chronic obstructive pulmonary disease: United States, 2013

MMWR Morb Mortal Wkly Rep

(2015)

R. Kessler et al.

“Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease

Am J Respir Crit Care Med

(2001)

A. Chaouat et al.

Pulmonary hypertension in COPD

Euro Respir J

(2008)

A. Chaouat et al.

Severe pulmonary hypertension and chronic obstructive pulmonary disease

Am J Respir Crit Care Med

(2005)

E. Weitzenblum et al.

Long-term course of pulmonary arterial pressure in chronic obstructive pulmonary disease

Am Rev Respir Dis

(1984)

R. Kessler et al.

Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

(1999)

S.K. Medrek et al.

Admission for COPD exacerbation is associated with the clinical diagnosis of pulmonary hypertension: results from a retrospective longitudinal study of a veteran population

COPD

(2017)

D. Hayes et al.

Prevalence of pulmonary hypertension and its influence on survival in patients with advanced chronic obstructive pulmonary disease prior to lung transplantation

COPD

(2016)

Cited by (22)

Reintubation After Lung Cancer Resection: Development and External Validation of a Predictive Score
2024, Annals of Thoracic Surgery
Citation Excerpt :
Our findings support the greater importance of Dlco%. Although FEV1% is mostly a measure of small airway function, Dlco% is a surrogate variable for alveolar perfusion and structural lung alteration.24 The value of Dlco% as an outcome predictor is supported by observation in patients with chronic obstructive pulmonary disease, where Dlco% predicted adverse outcomes more reliably than FEV1%.25
Reintubation after lung cancer resection is an important quality metric because of increased disability, mortality and cost. However, no validated predictive instrument is in use to reduce reintubation after lung resection. This study aimed to create and validate the PRediction Of REintubation After Lung cancer resection (PROREAL) score.
The study analyzed lung resection cases from 2 university hospitals. The primary end point was reintubation within 7 days after surgery. Predictors were selected through backward stepwise logistic regression and bootstrap resampling. The investigators used reclassification and receiver-operating characteristic (ROC) curve analyses to assess score performance and compare it with an established score for all surgical patients (Score for Prediction of Postoperative Respiratory Complications [SPORC]).
The study included 2672 patients who underwent resection for lung cancer (1754, development cohort; 918, validation cohort) between 2008 and 2020, of whom 71 (2.7%) were reintubated within 7 days after surgery. Identified score variables were surgical extent and approach, American Society of Anesthesiologists physical status, heart failure, renal disease, and diffusing capacity of the lung for carbon monoxide. The score achieved excellent discrimination in the development cohort (ROC AUC, 0.90; 95% CI, 0.87-0.94) and good discrimination in the validation cohort (ROC AUC, 0.74, 95% CI; 0.66-0.82), thus outperforming the SPORC in both cohorts (P < .001 and P = .018, respectively; validation cohort net reclassification improvement, 0.39; 95% CI, 0.18-0.60; P = .001). The score cutoff of ≥5 yielded a sensitivity of 88% (95% CI, 72-95) and a specificity of 81% (95% CI,79-83) in the development cohort.
A simple score (PROREAL) specific to lung cancer predicts postoperative reintubation more accurately than the nonspecific SPORC score. Operative candidates at risk may be identified for preventive intervention or alternative oncologic therapy.
Therapeutic potential and protective role of GRK6 overexpression in pulmonary arterial hypertension
2023, Vascular Pharmacology
Abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a key mechanism in the development of pulmonary arterial hypertension (PAH). Signal transducer and activator of transcription 3 (STAT3) signalling plays a critical role in modulating PASMC proliferation, and G-protein-coupled receptor kinase 6 (GRK6) regulates the STAT3 pathway. However, the mechanism underlying the relationship between GRK6 and PAH remains unclear. In this study, we aimed to investigate the role of GRK6 in PAH and determine its potential as a therapeutic target. We utilised hypoxia- and SU5416-induced PAH mouse models and a monocrotaline-induced PAH rat model to analyse the involvement of GRK6. We conducted gain- and loss-of-function experiments using mouse PASMCs. Modulation of GRK6 expression was achieved via a lentiviral vector in vitro and an adeno-associated virus serotype 1 encoding GRK6 in vivo. GRK6 was significantly downregulated in the lung tissues of PAH mice and rats, predominantly in PASMCs. Knockout of GRK6 exacerbated PAH, while both therapeutic and prophylactic overexpression of GRK6 alleviated PAH, as evidenced by a reduction in right ventricular systolic pressure, right ventricular wall to left ventricular wall plus ventricular septum ratio, pulmonary vascular media thickness, and pulmonary vascular muscularisation. Mechanistically, GRK6 overexpression attenuated hypoxia-induced PASMC proliferation and STAT3 phosphorylation. Conversely, knockdown of GRK6 promoted hypoxia-induced proliferation, which was mitigated by a STAT3 inhibitor. Our findings highlight the potential protective and beneficial roles of GRK6 in PAH; we propose a lung-targeted GRK6 gene therapy utilizing adeno-associated virus serotype 1 as a potential treatment approach for patients with PAH.
Burden of pulmonary hypertension due to chronic obstructive pulmonary disease: Analysis of exacerbations and healthcare resource utilization in the United States
2023, Respiratory Medicine
The burden of pulmonary hypertension (PH) among patients with chronic obstructive pulmonary disease (COPD) is not well understood. The present retrospective cohort study aimed to quantify the clinical and economic burden of PH in patients with COPD.
Adults with COPD were retrospectively identified in the Optum® Clinformatics® Data Mart between July 1, 2016 and June 30, 2021. Those diagnosed with PH were assigned to the PH-COPD cohort and those without a diagnosis of PH were assigned to the COPD cohort. Outcomes, including the number of visits for exacerbations and all-cause and COPD-related healthcare resource utilization (HCRU) and costs per patient per month (PPPM), were compared between cohorts. Baseline and study outcomes were analyzed descriptively. For significance testing, continuous variables were analyzed using Student's t-tests and categorical variables were analyzed using Chi-square tests.
A total of 1627 patients with PH-COPD were matched 1:1 to COPD patients without PH. A greater percentage of PH-COPD patients experienced COPD exacerbations vs. the COPD cohort (p < 0.001) and the PH-COPD cohort had more total (p < 0.001) and severe exacerbation-related visits PPPM (p < 0.001). All-cause and COPD-related HCRU PPPM estimates were higher among the PH-COPD cohort vs. the COPD cohort (p < 0.01). Total all-cause (p < 0.001) and COPD-related costs (p < 0.001) were higher among PH-COPD patients than COPD patients.
Patients with PH-COPD had higher rates of severe exacerbations, hospitalizations, and costs compared to COPD patients without PH, underscoring the need for targeted therapies to prevent and manage PH in patients with COPD.
Hemodynamic characteristics in patients with pulmonary hypertension and chronic obstructive pulmonary disease: A retrospective monocentric cohort study
2023, Respiratory Medicine and Research
Pulmonary hypertension (PH) is a hemodynamic condition characterized by an abnormal elevation in pulmonary arterial pressures. Several pathophysiological pre-capillary and post-capillary mechanisms have been described. PH is a common complication of chronic obstructive pulmonary disease (COPD), however, the prevalence of each mechanism in the development of PH in patients with COPD has been hardly studied.
We reported the clinical, functional, hemodynamic characteristics and outcomes of patients diagnosed with COPD and PH among the expert PH center of Nancy between January 1^st, 2015 and March 31^st, 2021.
123 patients with COPD and PH were included. Most patients (n=122, 99%) had a pre-capillary mechanism, 9% (n=11) a post-capillary mechanism, and 1% (n=1) an unclassified mechanism. 111 (90%) patients had pure pre-capillary PH and 11 (9%) patients had combined pre- and post-capillary PH. Combined pre- and post-capillary PH group was characterized by higher prevalence of cardiovascular comorbidities and of sleep apnea-hypopnea syndrome, a higher body mass index, lower lung volumes, higher mean pulmonary arterial pressure, pulmonary arterial wedge pressure and right atrial pressure. At follow-up (median 30 months), 52 patients had died, and 11 had undergone lung transplantation. One-year, three-year and five-year transplant-free survival rates were 71%, 29% and 11% respectively. There was no difference on outcomes between groups.
PH in COPD patients is mostly due to pre-capillary mechanism. However, the existence of various and numerous comorbidities in COPD, especially cardiovascular, can lead to the participation of post-capillary mechanisms in the development of PH. Further studies are needed to confirm these findings and to assess the impact on outcomes and management strategies in these different patients.
Severe Pulmonary Hypertension in COPD: Impact on Survival and Diagnostic Approach
2022, Chest
Citation Excerpt :
Multivariate analysis, however, identified only two independent predictors: 6-min walk distance, with a best predictive threshold at 200 m, and systemic pulmonary vascular resistance index, with the best predictive threshold at 2,800 dyn/s/cm5/m2. Of note, in this analysis, only patients with severe PH were included, which may explain why some previously described prognostic parameters for COPD or for group 3 PH, such as lung diffusion capacity for carbon monoxide19,20 or pulmonary artery enlargement,18,21-23 did not reach statistical significance. The fact that the absence of a high systemic pulmonary vascular resistance index was an independent predictor of poor prognosis in the multivariate analysis suggests that systemic vasodilation (eg, resulting from hypoxemia) may represent an important complication in these patients, which deserves further exploration.
Severe pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization.
Can noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease?
We retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex.
We included 142 patients with median FEV₁ of 55.0% predicted (interquartile range [IQR], 42.4%–69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27–43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH).
In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable.
Treatment of Pulmonary Hypertension Associated With COPD: Time for Another Look?
2021, Chest

View all citing articles on Scopus

: FUNDING/SUPPORT: This work was supported by the National Heart Lung and Blood Institute [grant T32 HL007534-36].

View full text

Chest

Original Research: Pulmonary and CardiovascularDiffusing Capacity Is an Independent Predictor of Outcomes in Pulmonary Hypertension Associated With COPD

Background

Research Question

Study Design and Methods

Results

Interpretation

Section snippets

Study Population and Design

Characteristics of a Patient With COPD-PH

Discussion

Acknowledgments

Chest

Chest

Respir Med

J Heart Lung Transplant

Lancet Respir Med

Chest

J Heart Lung Transplant

JACC Heart Fail

J Heart Lung Transplant

Chest

J Clin Epidemiol

J Am Coll Cardiol

J Heart Lung Transplant

Eur J Radiol

J Heart Lung Transplant

J Heart Lung Transplant

Chest

Heart Lung Circ

Chest

Am J Cardiol

Respir Med

Chest

Chest

Mortality in the United States, 2016

NCHS Data Brief

Employment and activity limitations among adults with chronic obstructive pulmonary disease: United States, 2013

MMWR Morb Mortal Wkly Rep

“Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease

Am J Respir Crit Care Med

Pulmonary hypertension in COPD

Euro Respir J

Severe pulmonary hypertension and chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Long-term course of pulmonary arterial pressure in chronic obstructive pulmonary disease

Am Rev Respir Dis

Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Admission for COPD exacerbation is associated with the clinical diagnosis of pulmonary hypertension: results from a retrospective longitudinal study of a veteran population

COPD

Prevalence of pulmonary hypertension and its influence on survival in patients with advanced chronic obstructive pulmonary disease prior to lung transplantation

COPD

Original Research: Pulmonary and Cardiovascular
Diffusing Capacity Is an Independent Predictor of Outcomes in Pulmonary Hypertension Associated With COPD