Sex Differences in Airways Result in Worse COPD Outcomes for Women, Study Says

Using computed tomography (CT), researchers illuminated structural differences in the airways of women compared with men which, in turn, result in worse outcomes in chronic obstructive pulmonary disease (COPD).

The results, published in Radiology, showed that in never-smokers, women had smaller airway lumen and that for ever-smokers, worsened lumen size resulted in worse respiratory outcomes in women than in men.

The authors noted that for women, prevalence of COPD is approaching that of men. Several theories for this have been proposed, including hormonal differences, more susceptibility to tobacco smoke and household biomass smoke, and genetic predisposition.

In addition, they have greater symptom burden and are less likely than men to be offered pulmonary rehabilitation, are more likely to be hospitalized, and have disparities in care compared with men.

For this study, the researchers aimed to investigate whether structural differences in airways may be responsible for some of these differences. They also wanted to probe possible sex predispositions to airway remodeling and impacts of airway remodeling on COPD outcomes. Therefore, CT measures of airway remodeling were analyzed in never-smokers, current smokers, and former smokers with and without airflow obstruction.

This study was a secondary analysis of the prospective multicenter observational cohort Genetic Epidemiology of COPD study (COPDGene). The COPDGene study ran from January 2008 to June 2011 and included current smokers, former smokers, and those who have never smoked between the ages of 45 and 80 years across 21 US clinical centers. The secondary analysis included all participants from round 1 of COPDGene (October 2006 to January 2011) and some never-smokers from round 2.

The researchers defined never-smokers as those who have smoked fewer than 100 cigarettes in their life and current smokers as those who have smoked cigarettes within 30 days of the study. Airflow obstruction was defined by a postbronchodilator forced expiratory volume in 1 second (FEV₁)-to-forced vital capacity (FVC) ratio of less than 0.70.

Among the 420 lifetime nonsmokers included in the study, 240 were women (57%) and 342 were non-Hispanic White (81%). Among the 9363 ever-smokers included, 5014 (54%) were men and 6292 (67%) were non-Hispanic White. The mean age for both groups was 60 years.

Researchers analyzed CT images of participants at full inspiration (total lung capacity). Airway disease was quantified using 7 different metrics:

• Airway wall thickness of segmental airways. Researchers calculated the mean airway wall thickness as the average airway wall thickness of 6 segmental bronchi for each participant.
• Wall area percent of segmental airways. This was calculated using the luminal area and total airway cross-sectional area for 6 segmental bronchi.
• The square root of the wall area of a hypothetical airway with 10-mm internal perimeter (Pi10). Pi10 was calculated to represent airway wall thickness that accounts for the size of the airways.
• Total airway count. Researchers calculated this by adding the number of identified branch points on the airway tree.
• Lumen diameter of segmental airways. Researchers calculated the average hydraulic diameter of segmental airways by multiplying the cross-sectional area by 4 and then dividing by the internal perimeter.
• Airway volume. This was estimated from airway trees segmented in the CT images.
• Airway fractal dimension. Researchers calculated this using the Minkowski-Boulgi box-counting dimension.

Researchers calculated least-squares mean values for each of these airway metrics and adjusted for age, height, ethnicity, body mass index, pack-years of smoking, current smoking status (ever- or never-smoker), total lung capacity at CT, display field of view on CT, and CT scanner type.

For ever-smokers, researchers also calculated associations between the 7 airway metrics and the ratio of forced expiratory volume in 1 second to forced vital capac, the modified Medical Research Council dyspnea scale, St George’s Respiratory Questionnaire score (which measures respiratory quality of life), and the 6-minute walk distance.

In never-smokers, men had thicker airway walls (measured by segmental airway wall thickness and segmental wall area percent) than women. There were no sex differences in airwall wall thickness in the Pi10 metric. The lumen parameters of airway volume, segmental airway diameters, total airway count, and airway fractal dimension metrics were all lower in women than in men among never-smokers.

In ever-smokers, men also had thicker airway walls (measured by segmental airway wall thickness and segmental wall area percent) than women. The lumen parameters of airway volume and airway fractural dimension metrics were also lower in women than in men among ever-smokers.

Higher wall thickness parameters and lower lumen metrics were associated with worse clinical outcomes in women than in men. A unit change in either greater wall thickness or lower lumen resulted in a lower FEV₁-to-FVC ratio in women than in men. A unit change in these 2 airway metrics (higher wall thickness or lower lumen measure) also resulted in more dyspnea, poorer respiratory quality of life, and lower 6-minute walk distance in women than in men. Each airway metric was also strongly associated with mortality more so in women than in men.

Limitations of this study include the higher proportion of active smoking men than active smoking women. The cross-sectional design to compare never-smokers and ever-smokers prevents researchers from determining causality to the airway changes. In addition, smaller airways could not be analyzed because of limited CT resolution.

Sex differences in airway structure and size, quantified at the time of CT scan and accounted for height and lung sizes, were observed in both never-smokers and ever-smokers and associated with worse outcomes in women than in men. “These structural differences may underlie some of the differences in predisposition to chronic obstructive pulmonary disease in men and women,” the researchers concluded.

Reference

Bhatt SP, Bodduluri S, Nakhmani A, et al. Sex differences in airways at chest CT: results from the COPDGene cohort. Radiology. 2022. doi: doi:10.1148/radiol.212985