Small Airway Disease in Pre-COPD and Early COPD: Insights Into the Pulmonary “Silent Zone”

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a life-course disorder with origins rooted in early-life insults. However, the current diagnostic reliance on the FEV1/FVC < 0.7 threshold often fails to capture the early phases of disease evolution, particularly within the pulmonary "Silent Zone." This narrative review examines small airway disease (SAD) in pre-COPD and early COPD by integrating physiological, structural, molecular, and diagnostic evidence. Findings from imaging and pathology studies indicate that terminal bronchiole loss, mucus plugging, alveolar attachment disruption, and vascular remodeling may occur before overt spirometric obstruction develops. We also summarize candidate molecular mechanisms that may contribute to early remodeling, including ATP5B-related epithelial signaling, STAT3/PINK1-Parkin-associated mitophagy, endothelial-to-mesenchymal transition, and inflammaging, while emphasizing that many of these pathways remain preliminary and require further validation. To bridge the diagnostic gap, we review multimodal approaches including FEV3-based indices, impulse oscillometry, parametric response mapping, CT-visible airway counts, and computational fluid dynamics. We further discuss clinical phenotypes such as PRISm and non-obstructive chronic bronchitis, as well as the contribution of non-tobacco environmental exposures. Overall, this review highlights how a Silent Zone-centered framework may improve early risk stratification and inform future studies aimed at disease modification before irreversible airflow obstruction develops.