COPD: Smoking, Emphysema Speed Lung Function Loss

The rate of change in forced expiratory volume in 1 second among patients with chronic obstructive pulmonary disease is highly variable, with the greatest rates of decline occurring among current smokers, patients with bronchodilator reversibility, and those with emphysema, according to an analysis of data from the ECLIPSE observational study reported online Sept. 26 in the New England Journal of Medicine.

Research in the 1970s established that patients with COPD experience an accelerated decline in FEV₁, yet few longitudinal studies have provided detailed data about this decline. Also, none have provided information about FEV₁ in specific subgroups of patients with COPD or according to levels of specific biomarkers.

Dr. Jørgen Vestbo of the University of Copenhagen and his colleagues analyzed data collected for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which included 2,163 patients aged 40-75 years who had a smoking history of 10 or more pack-years and 80% of the predicted value and ratio of FEV₁ to forced vital capacity (FVC) of 0.7 or less (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMoa1105482]).

Specifically, the researchers analyzed changes in FEV₁ after bronchodilator use at baseline, 3 months, 6 months, and then every 6 months for 3 years. They defined subgroups according to the presence of emphysema and chronic bronchitis, bronchodilator reversibility, and cardiovascular disease. They also obtained serum and plasma samples for the following biomarkers: C-reactive protein, interleukin-8, interleukin-6, fibrinogen, tumor necrosis factor–alpha, surfactant protein D, and Clara cell secretory protein 16 (CC-16).

The rate of FEV₁ was highly variable during the 3-year period, the results showed. Overall, there was a mean decline of 33 mL/year. More specifically, 38% of patients had a decline of more than 40 mL/year, 31% had a decline of 21-40 mL/year, 23% had changes ranging from a decline of 20 mL/year to an increase of 20 mL/year, and 8% had an increase of more than 20 mL/year.

The researchers also found an inverse relationship between the declines in FEV₁ and stage of disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Mean rates of decline were 35 mL/year in patients with moderate disease (GOLD stage 2), 33 mL/year in patients with severe disease (GOLD stage 3), and 25 mL/year in patients with very severe disease (GOLD stage 4).

Smoking status was most strongly associated with the rate of decline, with current smokers experiencing a decline of 21 mL/year more than former smokers. However, cumulative exposure did not affect future decline. "This finding points to smoking cessation as the most important tool in secondary and tertiary prevention for patients at all stages of COPD," the researchers said.

Among the subgroups studied, FEV₁ declined by 17 mL more per year in patients with bronchodilator reversibility at baseline, compared with those without reversibility. Also, FEV₁ declined by an additional 13 mL/year in patients with clinically significant emphysema versus those with little or no emphysema. The presence of cardiovascular disease had no effect on FEV₁.

Although several biomarkers were associated with FEV₁ at baseline, only CC-16 levels were significantly associated with the rate of change in FEV₁, with an additional decline of 4 mL/year for each decrease of 1 standard deviation in the level of CC-16. "This association was weak, and whether it is biologically meaningful has yet to be determined," Dr. Vestbo and his colleagues said. "Without confirmation, it does not seem appropriate to speculate on the potential significance of this finding."

The study findings call into question whether COPD is invariably progressive. "In more than half the patients in our study, the rate of decline in FEV₁ over a period of 3 years was no greater than that which has been observed in people without lung disease. This finding could indicate that COPD may ‘burn out’ or at least stabilize for periods of 3 years or more, which would be good news for patients and could influence a variety of management decisions that depend on prognosis."

A limitation of the study was that it included only patients with moderate, severe, or very severe COPD, and therefore could not identify factors associated with rates of decline in early-stage COPD. Also, the study was purely observational and did not include treatment. "Moreover, the diagnosis and management of COPD in the patients in our study were carried out at specialist centers, and our results may not extend beyond this patient population for a variety of reasons, including the clinically determined care they received," the researchers said.

In an editorial accompanying the report, Dr. Peter Burney said this longitudinal analysis "did not confirm the promise of the earlier cross-sectional analysis [Eur. Respir. J. 2008;31:869-73] by these investigators." One reason is that "association studies undertaken in clinical settings are likely to provide misleading results" because participants often have "coexisting illnesses that may result in spurious associations with the condition being investigated," he said (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMe1109130]).

In addition, "defining GOLD stage 1 disease as a ratio of FEV₁ to forced vital capacity (FVC) of less than 0.7, applied to all age groups, may lead to overreporting of abnormal ratios in older age groups and underreporting of them in younger age groups," said Dr. Burney of the National Heart and Lung Institute, Imperial College, London.

"Failure to distinguish between FEV₁ as a sign of obstruction and FEV₁ as a marker of low FVC has caused much confusion, mostly due to failure to measure or report FVC. It is almost certainly responsible for the association between ventilator function and markers of systemic inflammation in the cross-sectional data for ECLIPSE and has similarly led to inflated associations of ‘obstruction’ with increased all-cause mortality and cardiovascular events in so-called normal populations," Dr. Burney wrote.

As with other studies, he continued, this one showed that those who quit smoking have no clear loss of lung function over time, compared with nonsmokers, adding to the body of evidence that quitting smoking can reduce the rate of decline of lung function. The important message from ECLIPSE is that it is never too late to derive benefit from quitting smoking, although patients derive more benefits by doing so earlier, he noted.

The study was supported by grants from GlaxoSmithKline to Dr. Vestbo and several coauthors. Some of the coauthors are employees of and own stock in GlaxoSmithKline. All coauthors reported ties to numerous pharmaceutical companies, including AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer.

Dr. Burney disclosed receiving consulting fees from GlaxoSmithKline and lecture fees from Pfizer and Boehringer Ingelheim.

The rate of change in forced expiratory volume in 1 second among patients with chronic obstructive pulmonary disease is highly variable, with the greatest rates of decline occurring among current smokers, patients with bronchodilator reversibility, and those with emphysema, according to an analysis of data from the ECLIPSE observational study reported online Sept. 26 in the New England Journal of Medicine.

Research in the 1970s established that patients with COPD experience an accelerated decline in FEV₁, yet few longitudinal studies have provided detailed data about this decline. Also, none have provided information about FEV₁ in specific subgroups of patients with COPD or according to levels of specific biomarkers.

Dr. Jørgen Vestbo of the University of Copenhagen and his colleagues analyzed data collected for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which included 2,163 patients aged 40-75 years who had a smoking history of 10 or more pack-years and 80% of the predicted value and ratio of FEV₁ to forced vital capacity (FVC) of 0.7 or less (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMoa1105482]).

Specifically, the researchers analyzed changes in FEV₁ after bronchodilator use at baseline, 3 months, 6 months, and then every 6 months for 3 years. They defined subgroups according to the presence of emphysema and chronic bronchitis, bronchodilator reversibility, and cardiovascular disease. They also obtained serum and plasma samples for the following biomarkers: C-reactive protein, interleukin-8, interleukin-6, fibrinogen, tumor necrosis factor–alpha, surfactant protein D, and Clara cell secretory protein 16 (CC-16).

The rate of FEV₁ was highly variable during the 3-year period, the results showed. Overall, there was a mean decline of 33 mL/year. More specifically, 38% of patients had a decline of more than 40 mL/year, 31% had a decline of 21-40 mL/year, 23% had changes ranging from a decline of 20 mL/year to an increase of 20 mL/year, and 8% had an increase of more than 20 mL/year.

The researchers also found an inverse relationship between the declines in FEV₁ and stage of disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Mean rates of decline were 35 mL/year in patients with moderate disease (GOLD stage 2), 33 mL/year in patients with severe disease (GOLD stage 3), and 25 mL/year in patients with very severe disease (GOLD stage 4).

Smoking status was most strongly associated with the rate of decline, with current smokers experiencing a decline of 21 mL/year more than former smokers. However, cumulative exposure did not affect future decline. "This finding points to smoking cessation as the most important tool in secondary and tertiary prevention for patients at all stages of COPD," the researchers said.

Among the subgroups studied, FEV₁ declined by 17 mL more per year in patients with bronchodilator reversibility at baseline, compared with those without reversibility. Also, FEV₁ declined by an additional 13 mL/year in patients with clinically significant emphysema versus those with little or no emphysema. The presence of cardiovascular disease had no effect on FEV₁.

Although several biomarkers were associated with FEV₁ at baseline, only CC-16 levels were significantly associated with the rate of change in FEV₁, with an additional decline of 4 mL/year for each decrease of 1 standard deviation in the level of CC-16. "This association was weak, and whether it is biologically meaningful has yet to be determined," Dr. Vestbo and his colleagues said. "Without confirmation, it does not seem appropriate to speculate on the potential significance of this finding."

The study findings call into question whether COPD is invariably progressive. "In more than half the patients in our study, the rate of decline in FEV₁ over a period of 3 years was no greater than that which has been observed in people without lung disease. This finding could indicate that COPD may ‘burn out’ or at least stabilize for periods of 3 years or more, which would be good news for patients and could influence a variety of management decisions that depend on prognosis."

A limitation of the study was that it included only patients with moderate, severe, or very severe COPD, and therefore could not identify factors associated with rates of decline in early-stage COPD. Also, the study was purely observational and did not include treatment. "Moreover, the diagnosis and management of COPD in the patients in our study were carried out at specialist centers, and our results may not extend beyond this patient population for a variety of reasons, including the clinically determined care they received," the researchers said.

In an editorial accompanying the report, Dr. Peter Burney said this longitudinal analysis "did not confirm the promise of the earlier cross-sectional analysis [Eur. Respir. J. 2008;31:869-73] by these investigators." One reason is that "association studies undertaken in clinical settings are likely to provide misleading results" because participants often have "coexisting illnesses that may result in spurious associations with the condition being investigated," he said (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMe1109130]).

In addition, "defining GOLD stage 1 disease as a ratio of FEV₁ to forced vital capacity (FVC) of less than 0.7, applied to all age groups, may lead to overreporting of abnormal ratios in older age groups and underreporting of them in younger age groups," said Dr. Burney of the National Heart and Lung Institute, Imperial College, London.

"Failure to distinguish between FEV₁ as a sign of obstruction and FEV₁ as a marker of low FVC has caused much confusion, mostly due to failure to measure or report FVC. It is almost certainly responsible for the association between ventilator function and markers of systemic inflammation in the cross-sectional data for ECLIPSE and has similarly led to inflated associations of ‘obstruction’ with increased all-cause mortality and cardiovascular events in so-called normal populations," Dr. Burney wrote.

As with other studies, he continued, this one showed that those who quit smoking have no clear loss of lung function over time, compared with nonsmokers, adding to the body of evidence that quitting smoking can reduce the rate of decline of lung function. The important message from ECLIPSE is that it is never too late to derive benefit from quitting smoking, although patients derive more benefits by doing so earlier, he noted.

The study was supported by grants from GlaxoSmithKline to Dr. Vestbo and several coauthors. Some of the coauthors are employees of and own stock in GlaxoSmithKline. All coauthors reported ties to numerous pharmaceutical companies, including AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer.

Dr. Burney disclosed receiving consulting fees from GlaxoSmithKline and lecture fees from Pfizer and Boehringer Ingelheim.

The rate of change in forced expiratory volume in 1 second among patients with chronic obstructive pulmonary disease is highly variable, with the greatest rates of decline occurring among current smokers, patients with bronchodilator reversibility, and those with emphysema, according to an analysis of data from the ECLIPSE observational study reported online Sept. 26 in the New England Journal of Medicine.

Research in the 1970s established that patients with COPD experience an accelerated decline in FEV₁, yet few longitudinal studies have provided detailed data about this decline. Also, none have provided information about FEV₁ in specific subgroups of patients with COPD or according to levels of specific biomarkers.

Dr. Jørgen Vestbo of the University of Copenhagen and his colleagues analyzed data collected for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, which included 2,163 patients aged 40-75 years who had a smoking history of 10 or more pack-years and 80% of the predicted value and ratio of FEV₁ to forced vital capacity (FVC) of 0.7 or less (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMoa1105482]).

Specifically, the researchers analyzed changes in FEV₁ after bronchodilator use at baseline, 3 months, 6 months, and then every 6 months for 3 years. They defined subgroups according to the presence of emphysema and chronic bronchitis, bronchodilator reversibility, and cardiovascular disease. They also obtained serum and plasma samples for the following biomarkers: C-reactive protein, interleukin-8, interleukin-6, fibrinogen, tumor necrosis factor–alpha, surfactant protein D, and Clara cell secretory protein 16 (CC-16).

The rate of FEV₁ was highly variable during the 3-year period, the results showed. Overall, there was a mean decline of 33 mL/year. More specifically, 38% of patients had a decline of more than 40 mL/year, 31% had a decline of 21-40 mL/year, 23% had changes ranging from a decline of 20 mL/year to an increase of 20 mL/year, and 8% had an increase of more than 20 mL/year.

The researchers also found an inverse relationship between the declines in FEV₁ and stage of disease, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Mean rates of decline were 35 mL/year in patients with moderate disease (GOLD stage 2), 33 mL/year in patients with severe disease (GOLD stage 3), and 25 mL/year in patients with very severe disease (GOLD stage 4).

Smoking status was most strongly associated with the rate of decline, with current smokers experiencing a decline of 21 mL/year more than former smokers. However, cumulative exposure did not affect future decline. "This finding points to smoking cessation as the most important tool in secondary and tertiary prevention for patients at all stages of COPD," the researchers said.

Among the subgroups studied, FEV₁ declined by 17 mL more per year in patients with bronchodilator reversibility at baseline, compared with those without reversibility. Also, FEV₁ declined by an additional 13 mL/year in patients with clinically significant emphysema versus those with little or no emphysema. The presence of cardiovascular disease had no effect on FEV₁.

Although several biomarkers were associated with FEV₁ at baseline, only CC-16 levels were significantly associated with the rate of change in FEV₁, with an additional decline of 4 mL/year for each decrease of 1 standard deviation in the level of CC-16. "This association was weak, and whether it is biologically meaningful has yet to be determined," Dr. Vestbo and his colleagues said. "Without confirmation, it does not seem appropriate to speculate on the potential significance of this finding."

The study findings call into question whether COPD is invariably progressive. "In more than half the patients in our study, the rate of decline in FEV₁ over a period of 3 years was no greater than that which has been observed in people without lung disease. This finding could indicate that COPD may ‘burn out’ or at least stabilize for periods of 3 years or more, which would be good news for patients and could influence a variety of management decisions that depend on prognosis."

A limitation of the study was that it included only patients with moderate, severe, or very severe COPD, and therefore could not identify factors associated with rates of decline in early-stage COPD. Also, the study was purely observational and did not include treatment. "Moreover, the diagnosis and management of COPD in the patients in our study were carried out at specialist centers, and our results may not extend beyond this patient population for a variety of reasons, including the clinically determined care they received," the researchers said.

In an editorial accompanying the report, Dr. Peter Burney said this longitudinal analysis "did not confirm the promise of the earlier cross-sectional analysis [Eur. Respir. J. 2008;31:869-73] by these investigators." One reason is that "association studies undertaken in clinical settings are likely to provide misleading results" because participants often have "coexisting illnesses that may result in spurious associations with the condition being investigated," he said (N. Engl. J. Med. 2011 Sept. 26 [doi:10.1056/NEJMe1109130]).

In addition, "defining GOLD stage 1 disease as a ratio of FEV₁ to forced vital capacity (FVC) of less than 0.7, applied to all age groups, may lead to overreporting of abnormal ratios in older age groups and underreporting of them in younger age groups," said Dr. Burney of the National Heart and Lung Institute, Imperial College, London.

"Failure to distinguish between FEV₁ as a sign of obstruction and FEV₁ as a marker of low FVC has caused much confusion, mostly due to failure to measure or report FVC. It is almost certainly responsible for the association between ventilator function and markers of systemic inflammation in the cross-sectional data for ECLIPSE and has similarly led to inflated associations of ‘obstruction’ with increased all-cause mortality and cardiovascular events in so-called normal populations," Dr. Burney wrote.

As with other studies, he continued, this one showed that those who quit smoking have no clear loss of lung function over time, compared with nonsmokers, adding to the body of evidence that quitting smoking can reduce the rate of decline of lung function. The important message from ECLIPSE is that it is never too late to derive benefit from quitting smoking, although patients derive more benefits by doing so earlier, he noted.

The study was supported by grants from GlaxoSmithKline to Dr. Vestbo and several coauthors. Some of the coauthors are employees of and own stock in GlaxoSmithKline. All coauthors reported ties to numerous pharmaceutical companies, including AstraZeneca, Boehringer Ingelheim, Novartis, and Pfizer.

Dr. Burney disclosed receiving consulting fees from GlaxoSmithKline and lecture fees from Pfizer and Boehringer Ingelheim.