Smoking tobacco is the best-known risk factor for COPD risk factor, but recent data from a multitude of population-based observational studies show that only a minority of lifelong smokers develop COPD.   “Furthermore, 25% of COPD cases occur in people who were never smokers,” says Benjamin M. Smith, MD, MS. “These observations suggest that additional factors contribute to COPD risk. While other risk factors have been identified, such as air pollution, occupational exposures, and asthma, recent studies have suggested that early life factors might also contribute to COPD risk.”

In the 1970s, researchers noted that there was considerable variation in lung function among healthy adults. Investigators speculated that such variation may be due to a developmental mismatch between airway tree caliber and lung size, which they termed “dysanapsis.” They hypothesized that dysanapsis, if present, may contribute to lung disease susceptibility later in life.

Taking a Deeper Look

For a study published in JAMA, Dr. Smith and colleagues sought to determine if dysanapsis was a risk factor for COPD in people who did not smoke or possess other risk factors. “We hypothesized that dysanapsis might be a major risk factor for COPD,” Dr. Smith says. The study team performed detailed measurements in more than 6,500 older adults who participated in 3 studies that included smokers and nonsmokers with and without COPD.

The studies—which included the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study, and the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS)—assessed dysanapsis using lung CT scans. The MESA Lung study was conducted in 6 United States cities and included patients with an average age of 69 years. CanCOLD study participants were located in 9 Canadian cities and had an average age of 67 years. SPIROMICS was based in 12 U.S. medical centers and included people with an average age of 63 years. SPIROMICS also collected data on patients reporting 20 or more pack-years of smoking tobacco.

Assessing Key Findings

In the community-based 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 (Table). The association remained after considering standard COPD risk factors, including smoking, environmental and occupational pollutants, and asthma. When investigators focused on participants from the CanCOLD study who never smoked and on heavy smokers from the SPIROMICS study, they found that never smokers with COPD had smaller airways relative to lung size, whereas heavy smokers who did not have COPD had larger than normal airways.

“Using multiple large cohorts from the U.S. and Canada, we showed that dysanapsis was a major COPD risk factor—a finding that is on par with smoking and other standard risk factors,” says Dr. Smith. “People with smaller airway trees relative to lung size tended to have lower lung function and higher COPD risk, even among never smokers. Conversely, lifelong heavy smokers who did not have COPD tended to have larger than expected airway trees relative to lung size.”

Analyzing the Implications

Findings of the study may help explain why some lifelong heavy smokers do not develop COPD, but Dr. Smith says more work is needed. “While the harmful effects of smoking are well established and reducing smoking is essential to public health, we need to start thinking more broadly about the origins and pathophysiology of COPD if we want to better prevent and treat this heterogeneous disease,” he says. “In our study, we observed that patients with dysanapsis-related COPD had a very different prognosis in terms of lung function decline when compared with patients who had COPD related to traditional causes. In the future, gaining a better understanding of the biological basis of dysanapsis may lead to early life interventions that will help us promote the development of healthy and resilient lungs.”