These CT scans of airways (red) and lungs (black) show the spectrum of dysanapsis, with smaller airways in proportion to lung size (left) compared with normal size airways (middle), and larger than normal airways (right). [VIDA Apollo Software, courtesy of Eric A. Hoffman, PhD, Radiology, University of Iowa Carver College of Medicine]

The results of a study funded in part by the U.S. National Heart, Lung, and Blood Institute (NHLBI) suggest that abnormal lung development may explain why some non-smokers will develop the debilitating lung disorder chronic obstructive pulmonary disease and some heavy smokers do not. The researchers’ retrospective observational study in more than 6,500 older adults found that people with small airways relative to the size of their lungs may have a lower breathing capacity and, consequently, an increased risk for COPD, even if they don’t smoke or have any other risk factors.

“This work, stemming from the careful analysis of lung images of COPD patients, shows that an abnormal lung development may account for a large proportion of COPD risk among older adults,” said James Kiley, PhD, director of NHLBI’s Division of Lung Diseases. “More research is needed to understand what drives this occurrence and to devise possible interventions.”

Kiley and collaborators reported their findings in JAMA, in a paper titled, “Association of Dysanapsis With Chronic Obstructive Pulmonary Disease Among Older Adults.”

COPD is the fourth leading cause of death in the United States. The disease causes airflow blockage and breathing-related problems that can severely limit a person’s day-to-day activities. Smoking, asthma, and air pollution account for many COPD cases, but up to 30% of cases occur in people who never smoked, and only a minority of heavy smokers develop the disease, suggesting that there are other risk factors at play.

“Smoking tobacco is a major COPD risk factor, but despite decades of declining smoking rates in many countries, the corresponding decreases in disease burden have been modest,” the authors wrote, “Although other factors have been linked to COPD (e.g., second-hand smoke, environmental or occupational pollutants, asthma), much of the variation in COPD risk remains unexplained.”

There are some clues, however. A 30-year lung function trajectory study found that about half of older adults with COPD appeared to have low lung function early in life. When we breathe, air moves through the airways, beginning with the windpipe or trachea, which branches out to smaller airways called bronchi and bronchioles. Benjamin Smith, MD, a pulmonary physician in the department of medicine at Columbia University Irving Medical Center, who was involved in the newly reported study in JAMA, explained that as people grow, their airways are thought to develop in proportion to their lungs, but in some people, the airways grow smaller or larger than expected—condition called dysanapsis. The reasons for this are not clear. “Dysanapsis is believed to arise early in life, has been implicated in obstructive lung disease susceptibility …” the team noted.

As dysanapsis can be quantified using computed tomography (CT) imaging, the researchers carried out a study to examine whether small airways, measured as the ratio of mean airway lumen diameter to total lung volume (airway to lung ratio), might explain why some older patients develop COPD in the absence of common risk factors. A team led by Smith looked at the records of more than 6,500 older adults participating in three studies that included smokers and nonsmokers with and without COPD. Each of the three studies, the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), and the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study, assessed dysanapsis using CT scans of the lungs.

The MESA Lung study, based in six U.S. cities, included white, African American, Hispanic, and Chinese American people who were aged 69 years on average. The participants from the CanCOLD study had an average age of 67 years and came from nine Canadian cities. SPIROMICS, based at 12 U.S. medical centers, included people who were age 63 years on average and reported 20 or more pack-years of smoking.

In the MESA Lung and CanCOLD studies, participants with smaller airways relative to lung size were much more likely to develop COPD compared with those with the larger airways relative to lung size. The association remained after considering standard COPD risk factors, including smoking, pollutants, and asthma.

The researchers then focused on participants from the CanCOLD study who never smoked, and heavy smokers from the SPIROMICS study. Never smokers with COPD had much smaller airways relative to lung size, whereas the heavy smokers who did not have COPD had larger than normal airways.

“Dysanapsis quantified on CT was significantly associated with COPD risk among older adults in the community, with lower airway to lung ratio associated with higher COPD incidence,” the investigators noted. “This may help explain why only a minority of people with heavy smoking history develop COPD, and why up to 30% of COPD occurs among people who never smoked.”

The team acknowledged a number of limitations to their study, but concluded, “Among older adults, dysanapsis was significantly associated with COPD, with lower airway caliber relative to lung size associated with greater COPD risk.”

“These results show that small airways relative to lung size are a very strong risk factor for COPD,” said Smith, who is lead study author. With normal aging, lung function declines, so people who already have low lung function to begin with may develop COPD later in life, even if they don’t smoke, he explained, adding that the findings may also help explain why some lifelong heavy smokers do not develop COPD. People with larger airways relative to lung size may be able to withstand lung damage from smoking and still have enough breathing reserve to prevent them from developing COPD.

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