Small-Airway Obstruction and Emphysema in COPD

Published - Written by Daniela Lamas

For more than four decades, we have known that peripheral airway resistance is increased in emphysema. But it is unclear what changes lead to this increase in resistance. Do the airways simply narrow, or are they destroyed altogether? Without the technology to resolve this question, it has remained largely unanswered.

Until now. In this week’s issue of NEJM, John McDonough and colleagues harness the fields of lung transplantation and high-resolution CT scanning to conduct a study of emphysema’s pathophysiology – and conclude that small airways are indeed destroyed in patients with chronic obstructive pulmonary disease (COPD).

To conduct this study, the authors examined living patients, explanted emphysematous lungs and healthy lungs intended for transplant.

They enrolled 78 patients with COPD who were due to undergo multi-detector CT scans anyway as part of a study on lung cancer prevention. Patients had varying severity of disease. Most were in their late 50s to 60s, with a greater than 40 pack-year smoking history.  In addition to this patient pool, the authors collected data on 12 explanted lungs from patients who had undergone transplant for their emphysema and four control lungs that had been intended for transplant but had gone unmatched.

By using both living patients and lung specimens, they were able to examine the lung at two different levels of resolution.

For the patients with COPD undergoing high-resolution CT, the authors quantified the number of small airways (defined as airways measuring 2-2.5 mm in internal diameter).

They then used a different kind of high-resolution CT, which cannot be used clinically, to get an even closer look at the lung parenchyma, this time from the donated lung samples. Lung specimens were frozen, and the authors were able to follow the branching of the smallest airways to calculate the number and diameter of the terminal bronchioles.

What they found was that patients with worse COPD had fewer and narrower small airways.

In fact, the explanted lungs (from patients with emphysema undergoing transplant) had from 72 to 89% fewer terminal bronchioles (bronchioles that do not end in alveoli) than controls.  The patients with less severe COPD, too, had fewer and narrower small airways.

While it was not possible to determine whether small airway loss preceded emphysematous destruction of alveolar airspace, the authors postulated that the small airways were actually lost first.

Of note, the authors acknowledge that it’s possible CT was not a sensitive enough tool, and the airways were not destroyed altogether but in fact reduced to a lumen too small to be seen by CT. Either way, the functional impairment is likely the same.

They conclude: “There is widespread narrowing and loss of smaller conducting airways before the onset of emphysematous destruction…This process readily explains the observed increase…in small-airway resistance in patients with COPD.”

In an accompanying editorial, Wayne Mitzner, a physiologist who studies the lung at Johns Hopkins, argues that this study should change the way we think about and define emphysema, and offers a potential mechanism to explain the airway destruction.

Based on McDonough et al’s findings, he postulates that in emphysema it’s actually the small airways that are affected first, not the alveoli. The airway becomes inflamed, narrowed, and ultimately destroyed. Once it’s destroyed, the elastic fibers that usually support the alveoli loose their support and can no longer support the alveoli. Thus, the alveolar wall collapses and folds, creating bullae seen in COPD.

While there’s no clear clinical correlation, this mechanism might suggest there is a time for COPD patients– when the airway is narrowed but not yet destroyed – where behavioral change or medication administration could improve their lung function.

Indeed, a recent study published in the Journal by Jorgen Vestbo and colleagues looked at rate of change of FEV1 over time in COPD, and found as part of the disease’s history, some patients saw improvement in their lung function.

It’s possible that, taking these two studies together, these are the patients whose airways have narrowed but were not yet destroyed at the time they stopped smoking cigarettes, for example. Whether or not this is the case, McDonough’s study brings us one step closer to understanding a process that is, largely, unperceived until it is irreversible.

“This destruction occurs silently, very far in the lung periphery,” says pulmonologist and NEJM editor-in-chief Dr. Jeffrey Drazen.

Question: How could this physiological advance in understanding point the way toward better treatments for COPD?