Small-Airway Loss in COPD Accounts for Increased Resistance

VANCOUVER, B.C. – Narrowing and loss of small conducting airways precedes the onset of emphysematous destruction and likely accounts for the greatly increased peripheral airway resistance seen in patients with chronic obstructive pulmonary disease, according to new research reported in the Oct. 21 issue of the New England Journal of Medicine.

Previous studies have shown that peripheral airway resistance increases by a factor of 4 to 40 in patients with COPD, with small airways (less than 2 mm in diameter) being the major sites of obstruction. In this study, John E. McDonough, of the James Hogg Research Center at St. Paul’s Hospital, Vancouver, and colleagues used multidetector computed tomography (CT) and microCT to examine the relationship between the numbers and dimensions of small airways and emphysematous destruction in 78 patients who had various stages of COPD, according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. The patients had volunteered as part of a study of lung cancer prevention (N. Engl. J. Med. 2011;365:1567-75).

The findings "extend earlier reports by showing that there is both widespread narrowing and loss of smaller conducting airways before the onset of emphysematous destruction in both centrilobular and panlobular emphysema phenotypes of COPD," Mr. McDonough and colleagues said. "This process readily explains the observed increase by a factor of 4 to 40 in small-airway resistance in patients with COPD."

In addition to the 78 patients from the lung cancer prevention study, the researchers collected data on four deceased patients who each donated a lung for transplantation (controls), four patients with centrilobular emphysema who each donated a lung, and eight patients with panlobular emphysema who donated 10 lungs after lung transplantation.

On multidetector CT, the number of airways measuring 2.0-2.5 mm in diameter per lung pair was reduced in patients with GOLD stages 1 and 2 (mild and moderate) disease, compared with controls, Mr. McDonough and colleagues said. There was further reduction in patients with GOLD stages 3 and 4 (severe and very severe) disease.

"The comparison of the results for control samples and those for diseased lungs showed fewer airways measuring 2 to 2.5 mm in both centrilobular and panlobular emphysematous phenotypes of COPD," the researchers said.

The researchers also used microCT to measure the number and cross-sectional area of the small terminal bronchioles, and performed histologic analysis to count the number of small airways per square centimeter and to measure the thickness of airway walls.

On microCT, lungs from patients with the centrilobular emphysematous phenotype of COPD had a reduction of 99.7% in the terminal bronchiolar cross-sectional area per lung, compared with that of the control lungs, and a reduction of 89% in the total number of terminal bronchioles per lung. Explanted lungs from patients with the panlobular emphysema phenotype showed a reduction of 83% in total cross-sectional area and a reduction of 72% in the number of terminal bronchioles, compared with the controls.

Finally, the researchers compared the number and dimensions of terminal bronchioles at different levels of emphysematous destruction. The narrowing and loss of terminal bronchioles preceded emphysematous destruction, they found.

Limitations of microCT include the high radiation dose and the cost of the procedure. Also, the sample design in this study made it difficult to determine whether airways measuring 2.0-2.5 mm in diameter disappeared or "simply narrow[ed] to the point at which the airways were no longer visible at a spatial resolution of approximately 1 mm," the researchers said.

In 1985, the National Heart, Lung, and Blood Institute defined emphysema as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis," Wayne Mitzner, Ph.D., wrote in an editorial accompanying the report by Mr. McDonough and colleagues. This study, however, challenges that definition by finding that patients with various degrees of COPD have a narrowing and almost total loss of terminal bronchioles, sometimes with minimal quantifiable damage in the distal parenchyma, said Dr. Mitzner of the Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Baltimore.

Even though the authors suggest that small-airway damage probably occurs before emphysematous destruction, the study was cross-sectional and involved a limited number of subjects, so it is difficult to prove causality. For example, if alveolar walls weaken and become more distensible, they could contribute to narrowing of the inflamed bronchial arteries. Also, a seminal study by J.G. Leopold and J. Gough in 1957 found relatively few severely narrowed airways that led to emphysematous regions.

Whatever the initiating cause, it is difficult to determine how pathological changes affect the 3-D structure. For example, if terminal bronchioles disappear after being completely obstructed and degraded as dead tissue, how do the larger airways connect to the remaining distal acini? And, if the small airways just disappear, why do the larger upstream airways stay obstructed? This study was limited by the inability to identify airways with lumens below the resolution of the CT images (approximately 1-2 mm), so there may still be fibrous connections to the distal parenchyma.

A new definition of emphysema may be needed to reflect the involvement of small airways beyond the simple absence of obvious fibrosis. Permanent enlargement of the distal airspaces may serve only as a structural biomarker that is a secondary result of small-airway inflammation and destruction.

This study was supported by grants from the U.S. National Heart, Lung, and Blood Institute; the Canadian Institute of Health Research–Thoracic Imaging Network of Canada; the Canadian Collaborative Innovative Research Fund; GlaxoSmithKline; and the Lavin Family Supporting Foundation. Three of the authors have received grants, honorarium, service contracts, or travel reimbursement from GSK. The Lavin Family Foundation has provided grants to one author and research support to the institution of another. Dr. Mitzner is on grant review panels for and receives travel expenses from the National Institutes of Health. Further disclosures are available at nejm.org.

VANCOUVER, B.C. – Narrowing and loss of small conducting airways precedes the onset of emphysematous destruction and likely accounts for the greatly increased peripheral airway resistance seen in patients with chronic obstructive pulmonary disease, according to new research reported in the Oct. 21 issue of the New England Journal of Medicine.

Previous studies have shown that peripheral airway resistance increases by a factor of 4 to 40 in patients with COPD, with small airways (less than 2 mm in diameter) being the major sites of obstruction. In this study, John E. McDonough, of the James Hogg Research Center at St. Paul’s Hospital, Vancouver, and colleagues used multidetector computed tomography (CT) and microCT to examine the relationship between the numbers and dimensions of small airways and emphysematous destruction in 78 patients who had various stages of COPD, according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. The patients had volunteered as part of a study of lung cancer prevention (N. Engl. J. Med. 2011;365:1567-75).

The findings "extend earlier reports by showing that there is both widespread narrowing and loss of smaller conducting airways before the onset of emphysematous destruction in both centrilobular and panlobular emphysema phenotypes of COPD," Mr. McDonough and colleagues said. "This process readily explains the observed increase by a factor of 4 to 40 in small-airway resistance in patients with COPD."

In addition to the 78 patients from the lung cancer prevention study, the researchers collected data on four deceased patients who each donated a lung for transplantation (controls), four patients with centrilobular emphysema who each donated a lung, and eight patients with panlobular emphysema who donated 10 lungs after lung transplantation.

On multidetector CT, the number of airways measuring 2.0-2.5 mm in diameter per lung pair was reduced in patients with GOLD stages 1 and 2 (mild and moderate) disease, compared with controls, Mr. McDonough and colleagues said. There was further reduction in patients with GOLD stages 3 and 4 (severe and very severe) disease.

"The comparison of the results for control samples and those for diseased lungs showed fewer airways measuring 2 to 2.5 mm in both centrilobular and panlobular emphysematous phenotypes of COPD," the researchers said.

The researchers also used microCT to measure the number and cross-sectional area of the small terminal bronchioles, and performed histologic analysis to count the number of small airways per square centimeter and to measure the thickness of airway walls.

On microCT, lungs from patients with the centrilobular emphysematous phenotype of COPD had a reduction of 99.7% in the terminal bronchiolar cross-sectional area per lung, compared with that of the control lungs, and a reduction of 89% in the total number of terminal bronchioles per lung. Explanted lungs from patients with the panlobular emphysema phenotype showed a reduction of 83% in total cross-sectional area and a reduction of 72% in the number of terminal bronchioles, compared with the controls.

Finally, the researchers compared the number and dimensions of terminal bronchioles at different levels of emphysematous destruction. The narrowing and loss of terminal bronchioles preceded emphysematous destruction, they found.

Limitations of microCT include the high radiation dose and the cost of the procedure. Also, the sample design in this study made it difficult to determine whether airways measuring 2.0-2.5 mm in diameter disappeared or "simply narrow[ed] to the point at which the airways were no longer visible at a spatial resolution of approximately 1 mm," the researchers said.

In 1985, the National Heart, Lung, and Blood Institute defined emphysema as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis," Wayne Mitzner, Ph.D., wrote in an editorial accompanying the report by Mr. McDonough and colleagues. This study, however, challenges that definition by finding that patients with various degrees of COPD have a narrowing and almost total loss of terminal bronchioles, sometimes with minimal quantifiable damage in the distal parenchyma, said Dr. Mitzner of the Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Baltimore.

Even though the authors suggest that small-airway damage probably occurs before emphysematous destruction, the study was cross-sectional and involved a limited number of subjects, so it is difficult to prove causality. For example, if alveolar walls weaken and become more distensible, they could contribute to narrowing of the inflamed bronchial arteries. Also, a seminal study by J.G. Leopold and J. Gough in 1957 found relatively few severely narrowed airways that led to emphysematous regions.

Whatever the initiating cause, it is difficult to determine how pathological changes affect the 3-D structure. For example, if terminal bronchioles disappear after being completely obstructed and degraded as dead tissue, how do the larger airways connect to the remaining distal acini? And, if the small airways just disappear, why do the larger upstream airways stay obstructed? This study was limited by the inability to identify airways with lumens below the resolution of the CT images (approximately 1-2 mm), so there may still be fibrous connections to the distal parenchyma.

A new definition of emphysema may be needed to reflect the involvement of small airways beyond the simple absence of obvious fibrosis. Permanent enlargement of the distal airspaces may serve only as a structural biomarker that is a secondary result of small-airway inflammation and destruction.

This study was supported by grants from the U.S. National Heart, Lung, and Blood Institute; the Canadian Institute of Health Research–Thoracic Imaging Network of Canada; the Canadian Collaborative Innovative Research Fund; GlaxoSmithKline; and the Lavin Family Supporting Foundation. Three of the authors have received grants, honorarium, service contracts, or travel reimbursement from GSK. The Lavin Family Foundation has provided grants to one author and research support to the institution of another. Dr. Mitzner is on grant review panels for and receives travel expenses from the National Institutes of Health. Further disclosures are available at nejm.org.

VANCOUVER, B.C. – Narrowing and loss of small conducting airways precedes the onset of emphysematous destruction and likely accounts for the greatly increased peripheral airway resistance seen in patients with chronic obstructive pulmonary disease, according to new research reported in the Oct. 21 issue of the New England Journal of Medicine.

Previous studies have shown that peripheral airway resistance increases by a factor of 4 to 40 in patients with COPD, with small airways (less than 2 mm in diameter) being the major sites of obstruction. In this study, John E. McDonough, of the James Hogg Research Center at St. Paul’s Hospital, Vancouver, and colleagues used multidetector computed tomography (CT) and microCT to examine the relationship between the numbers and dimensions of small airways and emphysematous destruction in 78 patients who had various stages of COPD, according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. The patients had volunteered as part of a study of lung cancer prevention (N. Engl. J. Med. 2011;365:1567-75).

The findings "extend earlier reports by showing that there is both widespread narrowing and loss of smaller conducting airways before the onset of emphysematous destruction in both centrilobular and panlobular emphysema phenotypes of COPD," Mr. McDonough and colleagues said. "This process readily explains the observed increase by a factor of 4 to 40 in small-airway resistance in patients with COPD."

In addition to the 78 patients from the lung cancer prevention study, the researchers collected data on four deceased patients who each donated a lung for transplantation (controls), four patients with centrilobular emphysema who each donated a lung, and eight patients with panlobular emphysema who donated 10 lungs after lung transplantation.

On multidetector CT, the number of airways measuring 2.0-2.5 mm in diameter per lung pair was reduced in patients with GOLD stages 1 and 2 (mild and moderate) disease, compared with controls, Mr. McDonough and colleagues said. There was further reduction in patients with GOLD stages 3 and 4 (severe and very severe) disease.

"The comparison of the results for control samples and those for diseased lungs showed fewer airways measuring 2 to 2.5 mm in both centrilobular and panlobular emphysematous phenotypes of COPD," the researchers said.

The researchers also used microCT to measure the number and cross-sectional area of the small terminal bronchioles, and performed histologic analysis to count the number of small airways per square centimeter and to measure the thickness of airway walls.

On microCT, lungs from patients with the centrilobular emphysematous phenotype of COPD had a reduction of 99.7% in the terminal bronchiolar cross-sectional area per lung, compared with that of the control lungs, and a reduction of 89% in the total number of terminal bronchioles per lung. Explanted lungs from patients with the panlobular emphysema phenotype showed a reduction of 83% in total cross-sectional area and a reduction of 72% in the number of terminal bronchioles, compared with the controls.

Finally, the researchers compared the number and dimensions of terminal bronchioles at different levels of emphysematous destruction. The narrowing and loss of terminal bronchioles preceded emphysematous destruction, they found.

Limitations of microCT include the high radiation dose and the cost of the procedure. Also, the sample design in this study made it difficult to determine whether airways measuring 2.0-2.5 mm in diameter disappeared or "simply narrow[ed] to the point at which the airways were no longer visible at a spatial resolution of approximately 1 mm," the researchers said.

In 1985, the National Heart, Lung, and Blood Institute defined emphysema as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis," Wayne Mitzner, Ph.D., wrote in an editorial accompanying the report by Mr. McDonough and colleagues. This study, however, challenges that definition by finding that patients with various degrees of COPD have a narrowing and almost total loss of terminal bronchioles, sometimes with minimal quantifiable damage in the distal parenchyma, said Dr. Mitzner of the Program in Respiratory Biology and Lung Disease, Johns Hopkins University, Baltimore.

Even though the authors suggest that small-airway damage probably occurs before emphysematous destruction, the study was cross-sectional and involved a limited number of subjects, so it is difficult to prove causality. For example, if alveolar walls weaken and become more distensible, they could contribute to narrowing of the inflamed bronchial arteries. Also, a seminal study by J.G. Leopold and J. Gough in 1957 found relatively few severely narrowed airways that led to emphysematous regions.

Whatever the initiating cause, it is difficult to determine how pathological changes affect the 3-D structure. For example, if terminal bronchioles disappear after being completely obstructed and degraded as dead tissue, how do the larger airways connect to the remaining distal acini? And, if the small airways just disappear, why do the larger upstream airways stay obstructed? This study was limited by the inability to identify airways with lumens below the resolution of the CT images (approximately 1-2 mm), so there may still be fibrous connections to the distal parenchyma.

A new definition of emphysema may be needed to reflect the involvement of small airways beyond the simple absence of obvious fibrosis. Permanent enlargement of the distal airspaces may serve only as a structural biomarker that is a secondary result of small-airway inflammation and destruction.

This study was supported by grants from the U.S. National Heart, Lung, and Blood Institute; the Canadian Institute of Health Research–Thoracic Imaging Network of Canada; the Canadian Collaborative Innovative Research Fund; GlaxoSmithKline; and the Lavin Family Supporting Foundation. Three of the authors have received grants, honorarium, service contracts, or travel reimbursement from GSK. The Lavin Family Foundation has provided grants to one author and research support to the institution of another. Dr. Mitzner is on grant review panels for and receives travel expenses from the National Institutes of Health. Further disclosures are available at nejm.org.