At the root:Defining and halting progression of early chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder with varying presentations and progression, but limited disease-modifying therapies. Trajectories of lung function decline in COPD differ significantly between individuals, with differences detectable in young adulthood. “Early disease” (initial manifestations in young individuals) should be distinguished from “late mild disease” (disease of mild severity in older individuals potentially present for decades). For research purposes, we propose an operational definition of early COPD: ever-smokers (≥10 pack-years) younger than 50 years with any of these abnormalities: (1) FEV1/FVC< lower limit of normal; (2) compatible CT abnormalities (airway abnormality and/or emphysema); or (3) FEV1 decline (≥60 mL/year). Biological underpinnings of early COPD are quite complex. Recent evidence implies that cigarette smoke-exposure induces sequential, stereotypical changes in distal airways, initially without inflammatory cell infiltration. Epithelial reprogramming is associated with mucus that is less readily cleared and with polymeric immunoglobulin receptor down-regulation accompanied by focal airway injury. Resulting differences in the community structure of the lung microbiome may be mechanistically important. Global gene analysis suggests that tissue degradation around small airways predominates over repair. Emphysema might also develop in early COPD due to loss of pulmonary endothelial cell-derived factors. To reduce COPD’s long-term societal impact, the goal of interventions must change, from solely focusing on reducing symptoms and exacerbations in advanced disease, to halting pathological progression in early disease. This review attempts to stimulate studies investigating younger smokers to understand the causes, progression, clinical expression and potential therapeutic targets of early COPD.