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Lung Development May Explain Who Is at Higher Risk for COPD


Up to 30% of cases of dysanapsis, having a small airway-to-lung ratio, occur in people who have never smoked, while not having the condition could explain why some heavy smokers never develop chronic obstructive pulmonary disease (COPD).

Individuals with dysanapsis, a condition where airways are small relative to lung size, may have an increased risk of chronic obstructive pulmonary disease (COPD) even if they don’t have other risk factors, according to a new study published in JAMA.

There is much that is unexplained about who and who does not develop COPD, the authors noted. Some hints have come from previous research, which has indicated that about 50% of older adults with COPD appeared to have low lung function early in life.

Although smoking, air pollution, or comorbid asthma are risk factors for COPD, up to 30% of cases occur in those who never smoked. In addition, only a minority of heavy smokers develop the disease, and while rates of smoking are declining, COPD remains a highly prevalent chronic disease.

This retrospective observational study involved 6529 older adults in 2 community-based samples. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study consisted of 2531 US participants across 6 sites. Participants included white, African American, Hispanic, and Chinese American people with a mean age of 69. The Canadian Cohort of Obstructive Lung Disease (CanCOLD) consisted of 1272 participants with a mean age of 67 across 9 Canadian sites.

In addition, a case-control study of COPD: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) involved 2726 participants across 12 US sites. This study included people who reported 20 or more pack-years of smoking and had a mean age of 63.

The airway-to-lung ratio was measured on CT as the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume. COPD was defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV1:FVC) less than 0.70 with respiratory symptoms.

Longitudinal lung function was the secondary outcome. The researchers adjusted results for demographics and standard COPD risk factors.

Even after including those risk factors, 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 in the MESA Lung and CanCOLD studies.

Looking at the participants from the CanCOLD study who never smoked and heavy smokers from the SPIROMICS study, the researchers found that never-smokers with COPD had much smaller airways relative to lung size.

Heavy smokers who did not have COPD had larger than normal airways, which leads researchers to think that they have more capacity to withstand the damage that smoking creates, they said. Among older adults, dysanapsis was significantly associated with COPD, with lower airway-to-lung ratio associated with greater COPD risk.

Individuals "with smaller than predicted airway tree size who never smoked may require no additional risk factor to meet the spirometric criteria for COPD," the authors wrote.

The study was funded in part by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

“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, in a statement. “More research is needed to understand what drives this occurrence and to devise possible interventions.”


Smith BM, Kirby M, Hoffman EA, et al. Association of dysanapsis with chronic obstructive pulmonary disease among older adults. JAMA. JAMA. 2020;323(22):2268-2280. doi:10.1001/jama.2020.6918

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