Computed tomography quantification of airway remodelling in normal ageing subjects: a cross-sectional study

To the Editor:

Airway remodelling inducing structural and functional decline is a main factor leading to clinical disablement in chronic obstructive pulmonary disease (COPD) [1]. However, whether airway remodelling is also a potential feature of the normal healing process in ordinary lifelong environmental exposure and chronic endogen damage due to senescence is not well elucidated [2]. The relationship between ageing and development of COPD is complex. On one hand, while there is a higher prevalence of COPD in the elderly, ageing is not the direct cause of COPD; on the other hand, it does increase the susceptibility of the lung to extrinsic damage [3].

To avoid misinterpretation in chest computed tomography (CT) analysis, physiological, age-related changes [4] should be recognised. Thus, the purpose of this prospective study was to evaluate whether airway remodelling resulting from the normal ageing process can be assessed in vivo using software-assisted CT quantification, with correlation to pulmonary function testing (PFT).

This study was conducted with the approval of the local research ethics committee. Participants were required to be asymptomatic, aged from 60 to 90 years, and nonsmokers for ≥20 years, with a cumulative history of <10 pack-years of tobacco use.

Subjects were excluded if they met any of the following criteria: cognitive disorders; past or current respiratory disease; congestive heart failure or myocardial infarction during the past year; chest radiotherapy; current or previous treatment with medication known to cause lung toxicity; former occupational exposure to asbestos or coal dust, or having any other occupational activity known to be related to lung disease.

CT acquisitions were spirometrically controlled (Winspiro, Waukesha, WI, USA) and performed on a 64 detector row CT scan unit (LightSpeed VCT; GE Healthcare, Little Chalfont, UK) without contrast material. The whole chest volume was acquired at total lung capacity for inspiratory CT, whereas for expiratory CT, only four incremental slices were performed at residual volume: one through the upper lobes, one through the tracheal carina, and two between the tracheal carina and the right diaphragmatic dome.

Data were anonymously processed by two radiologists (S. Bommart and F. Klein). The inspiratory CT acquisition was computed using commercially available CT software (Thoracic VCAR; GE Healthcare). This software performs automated tracking of the airways providing cross-sectional views perpendicular to each bronchus long axis, and subsequently measures the bronchial lumen and wall. Proximal airway analysis included three different segmental bronchi: the right apical bronchus (B1), the anterior basal bronchus (B8) and the posterior basal bronchus (B10) were arbitrarily chosen to be the site of the automated measurements. The lumen area (LA), wall area (WA), wall thickness (WT) and total diameter of the bronchus (WD) were automatically displayed at a site chosen by the radiologist, at mid-distance between the origin of the segmental bronchus and its first division. WT/WD and WT/WA ratios for each segment, and the square root of WA for a standardised airway with an internal perimeter of 10 mm (Pi10) were calculated [5]. Air trapping was quantified using software (Myrian; Intrasense, Montpellier, France) based on threshold techniques. Expiratory/inspiratory ratios of mean lung density (MLD) were calculated [6].

Subjects also underwent spirometry using a whole-body plethysmograph (Body Box; Medisoft, Dinant, Belgium) according to current guidelines [7]. Single-breath nitrogen testing (SBNT) was performed using the Vmax apparatus (Sensormedics, Yorba Linda, CA, USA) [8, 9].

The airway measures were modelled as a function of age. Univariate analyses were carried out using Spearman correlations and linear regressions.

This single-centre observational study enrolled 101 consecutive community-based volunteers, recruited between August 2009 and April 2012. 11 were unable to perform adequate respiratory manoeuvres during PFT and/or spirometrically controlled chest CT, and were thus excluded. Subjects were also excluded when PFT abnormalities were suggestive of undiagnosed lung disease according to American Thoracic Society/European Respiratory Society criteria. The final study group consisted of 89 individuals with a mean±sd age of 71.7±7.9 years including 52 women and 28 former light smokers (mean 0.4 pack-years). Automated airway tree skeletonisation and proximal airway segmentation were achievable for 81 (91%) inspiratory CT scans. Air trapping calculation was obtained using both expiratory and inspiratory image sets.

Results of a univariate analysis of the relationship between airway measures and age, together with other clinical characteristics, are presented in table 1. Of the different airway measurements, only the LA values obtained at the fourth generation of B10 were related to age (p=0.03), together with the WD/WT and WT/WA ratios in B10 at the fourth and fifth generations (p<0.05). No relationship was found for the other parameters of airway dimensions or Pi10 values. CT air trapping was correlated to age (p<0.0001, correlation coefficient 0.48, R²=0.2). The MLD of the whole inspiratory lung volume was 831.59±19.25 HU and the proportion of voxels below the −950-HU threshold was 0.98±0.87%; neither was related to age (p=0.21 and p=0.42, respectively).

In this study, which explored the impact of ageing on airway remodelling, we found ageing mainly affected the distal airways, with demonstration of a close relationship between CT-quantified air trapping and age in healthy volunteers >60 years of age. Our findings suggest that structural changes are heterogeneous and that the ageing process, which involves the whole airway tree, is more pronounced at the level of the distal airways. The relationship between SBNT-derived parameters and age corroborates the prominent role of distal remodelling [10].

We did not identify a linear progression of wall thickening related to age between the fourth and the sixth generation as that suggested to exist in COPD [11]. Moreover, Pi10 was not related to age in our population. This suggests that physiological ageing and COPD affect the airway tree differently.

This study had several limitations. Only three segments between the fourth and the sixth generation in the right lung were analysed to assess a potential regional heterogeneity of the ageing process at the proximal level. For our sampling, we chose to evaluate bronchi away from paracardiac segments to avoid bronchial wall blurring due to cardiac motion artefacts. We did not perform bronchial measurements beyond the sixth generation because of their reported unreliability [12]. The second limitation is that expiratory CT was limited to a four-slice CT acquisition and did not consist of a volumetric whole-lung expiratory CT acquisition, in order to minimise the radiation exposure of our healthy volunteers. However, the four-slice sampling was sufficient to measure air trapping, which correlated well with functional indexes of small airway obstruction for each of the four levels [4].

Lastly, we were not able to elucidate the mechanism of distal airway obstruction reflected by air trapping, due to the limits of CT resolution. We might suspect it is due to bronchial thickening, as this phenomenon was found at a more proximal level, but we cannot affirm it is the main or unique cause of distal obstruction. In conclusion, the present study involving an asymptomatic healthy population aged between 60 and 90 years suggests that airway remodelling with age is a heterogeneous process having a particular tropism towards distal airways. Knowledge of this process can help distinguishing early changes in COPD or other diseases affecting the distal airways from normal ageing.