Understanding physiological and computed tomography measures of small airways disease and their clinical relevance in chronic obstructive pulmonary disease

Abstract

Small airways disease (SAD) is a multifactorial pathological process, central to the development of Chronic Obstructive Pulmonary Disease (COPD). Physiological manifestations of SAD can be measured using in-depth lung function and imaging while in vivo airway sampling can help gain insight into disease mechanisms. However, there is no gold standard or specific marker of SAD. This thesis compared physiological and CT approaches to quantify SAD and examined their relationship with distal lung inflammatory cells to determine if they can be used to gain insight into disease endotypes. Furthermore, it aimed to ascertain their clinical relevance in mild/moderate COPD.

In non-smokers, ex-smokers and mild/moderate COPD subjects (divided into infrequent and frequent exacerbators), in-depth lung function testing and CT image analyses using densitometry, Disease Probability Mapping (DPM) and Parametric Response Mapping (PRM) quantified SAD. Lung function testing included Multiple Breath Nitrogen Washout (MBNW) and Forced Oscillation Technique (FOT) among other tests and was performed before and after bronchodilation. Subjects underwent bronchoscopy and the inflammatory cell profile in bronchoalveolar lavage was analysed. Further lung function testing was performed at a follow up visit one year after bronchoscopy to assess any changes in small airways function over time.

The findings confirmed physiological indices of SAD are abnormal in COPD compared to health but not different between non and ex-smokers. These indices are stable over one year but do show change with bronchodilators in some COPD subjects. Novel findings included increased acinar ventilation heterogeneity in frequent compared to infrequent exacerbators. A systematic review revealed there were no studies comparing CT, FOT and MBNW indices of SAD in COPD. This study was therefore the first to compare co-registration CT techniques with FOT and MBNW indices and found FOT and MBNW indices of SAD did not predict CT defined SAD, in COPD. Significant associations between indices of SAD and distal neutrophilic inflammation were found in frequent not infrequent exacerbators. Lung de-recruitment derived during FOT begins at a higher lung volume in COPD compared to health. In COPD, indices of SAD not emphysema predict the onset of de-recruitment. Indices of SAD in this thesis did not associate with patient reported outcomes or functional assessment.
This study data suggests quantitative indices of SAD in COPD may measure or represent different aspects of a multifaceted dysfunction. However, these indices have potential to give insight into COPD endotypes and may be used in future to evaluate therapeutic intervention targeted to this area.

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Identifiers

ORCID for Joy H Conway: orcid.org/0000-0001-6464-1526

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