With age comes increased risk for those with dysanapsis

Smoking is undoubtedly the number one cause of chronic obstructive pulmonary disease (COPD), but not every COPD patient is a current or former smoker, so what is the likely cause of COPD in those cases? A likely answer, according to researchers who published their findings in JAMA, is a mismatch that occurs during lung development.

Some people have airways that are too small to adequately serve their lung capacity, explained Benjamin M. Smith, MD, MS, of McGill University Health Centre Research Institute in Montreal, Quebec and Columbia University Irving Medical Center in New York, and colleagues. As a result of this dysanapsis, when these individuals age they have an increased risk for COPD.

That finding emerged from a retrospective analysis of data collected by the 2,531-person Multi-Ethic Study of Atherosclerosis (MESA), the Canadian Cohort of Obstructive Lung Disease (n=1,272) and SPIROMICS, a 2,726-person case control study of COPD.

The study was supported in part by the National Heart Lung and Blood Institute, which released a statement on the study. “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,” James Kiley, Ph.D., director of NHLBI’s Division of Lung Diseases said in the prepared statement. “More research is needed to understand what drives this occurrence and to devise possible interventions.”

Using CT scans, the researchers quantified dysanapsis as “the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume (airway to lung ratio).” The primary outcome was COPD, “defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV1:FVC) less than 0.70 with respiratory symptoms. Secondary outcome was longitudinal lung function… Spirometry was repeated prospectively over a median of 6.2 years in MESA lung (1458 of 2531 [57.6%]), 3.1 years in CanCOLD (1032 of 1272 [81.1%]), and 2.1 years SPIROMICS (2139 of 2726 [78.5%]).”

A little more than half the participants in the MESA study were women (52.7%) and the mean age of all participants was 69. About one in ten participants (n=237) had prevalent COPD: “the mean (SD) airway to lung ratio was 0.033 (0.004), and the mean (SD) FEV1 decline was −33 mL/y (31 mL/y).”

Among the 2,294 MESA without prevalent COPE, 98 developed COPD after a median of 6.2 years. “Compared with participants in the highest quartile of airway to lung ratio, those in the lowest had a significantly higher COPD incidence (9.8 versus 1.2 cases per 1000 person-years; rate ratio [RR], 8.12; 95% CI, 3.81-17.27; rate difference, 8.6 cases per 1000 person-years; 95% CI, 7.1-9.2; P < .001) but no significant difference in FEV1 decline (−31 versus −33 mL/y; difference, 2 mL/y; 95% CI, −2 to 5; P = .30),” Smith et al wrote.

There were fewer women in the CanCOLD study — 564, which was 44.3% of the cohort — and mean age was 67. More of the CanCOLD participants had incident COPD at 15.0%, which developed at median of 3.1 years. “The COPD incidence in the lowest airway to lung quartile was significantly higher than in the highest quartile (80.6 vs 24.2 cases per 1000 person-years; RR, 3.33; 95% CI, 1.89 to 5.85; rate difference, 56.4 cases per 1000 person-years; 95% CI, 38.0 to 66.8; P<.001), but the FEV1 decline did not differ significantly (−34 vs −36 mL/y; difference, 1 mL/y; 95% CI, −15 to 16; P=.97),” they wrote.

And, looking at the 1,206 SPIROMICS patients, the mean age was 65. Among the 542 women with COPD in SPIROMICS who were followed for 2.1 years, “those in the lowest airway to lung ratio quartile had a mean FEV1 decline of −37 mL/y (15 mL/y), which did not differ significantly from the decline in MESA Lung participants (P = .98), whereas those in highest quartile had significantly faster decline than participants in MESA Lung (−55 mL/y [16 mL/y ]; difference, −17 mL/y; 95% CI, −32 to −3; P =.004),” the study authors wrote. “These results show that small airways relative to lung size are a very strong risk factor for COPD,” said Smith in the prepared statement from the NHLBI. “This helps us to understand why 30% of COPD can occur in people who never smoked.” 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.

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Smith and colleagues spelled out nine limitations to their findings, including the fact that the “airway to lung ratio was assessed after the period of lung development,” and the airway to lung ratio measure “may partly reflect emphysema-associated loss of airway tethering, airway remodeling, or lung hyperinflation.”

Additionally, “disease progression is multidimensional, but the present analysis focused on lung function decline,” they wrote. “Fourth, unmeasured, imprecisely measured, or differential susceptibility to COPD risk factors that alter the airway to lung ratio may inflate associations with COPD… Fifth, the airway tree reference equations were derived from a subset of participants included in the main association analyses of the MESA Lung study, which may affect generalizability… Sixth, the variance statistically accounted for and the NRI used to quantify the importance of the airway to lung ratio relative to other risk factors depend in part on study-specific associations and risk factor and outcome distributions; … Seventh, COPD status assessed at study visits (interval censoring) may have biased the COPD rate ratio estimates toward the null but would affect equally the estimates for the airway to lung ratio measure and other COPD risk factors. Eighth, differences among participants with missing baseline or follow-up data may introduce bias and limit generalizability… Ninth, it is possible that the findings in established COPD may be confounded by selection on COPD, a type of collider or index case bias.”

  1. Among older adults, dysanapsis appears to be a risk factor associated with COPD.

  2. This finding suggests that lung function declines associated with normal aging may increase the risk for COPD later in life, even among non-smokers.

Peggy Peck, Editor-in-Chief, BreakingMED™

Smith reported receiving grants from the National Institutes of Health (NIH), Canadian Institutes of Health Research (CIHR), Fonds de la recherche en santé du Québec (FRQS), the Research Institute of the McGill University Health Centre, and the Quebec Lung Association and winning an investigator-initiated operating grant from AstraZeneca.

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