An Integrated Biological Model for Precision Pulmonary Rehabilitation in COPD

Pulmonary rehabilitation improves symptoms, exercise capacity and quality of life in chronic obstructive pulmonary disease (COPD), although patients with similar clinical characteristics often show different responses. This review summarizes the biological determinants of rehabilitation responsiveness identified through more than 10 years of translational research. Evidence from longitudinal studies of elderly patients with severe COPD undergoing standardized pulmonary rehabilitation was integrated with clinical, functional, molecular, immunological, cognitive, behavioural and lifestyle data, including long-term follow-up. Baseline DNA damage was markedly increased and further rose during rehabilitation (19.6 ± 7.3% vs. 21.8 ± 7.2% tail intensity) despite significant functional improvement. FKBP5 rs4713916 was the only genetic variant associated with better rehabilitation outcomes. Daily vegetable intake independently predicted treatment success, whereas smoking was associated with oxidative DNA damage, immune alterations and higher Torque Teno Virus (TTV) load. TTV ≥ 4 log10 copies/mL was associated with increased regulatory T cells, reduced α7 nicotinic acetylcholine receptor expression (31% vs. 52%; p = 0.023) and shorter 5-year survival (609 ± 160 vs. 937 ± 94 days; p = 0.017). Active Coping, Planning and Self-Distraction were the behavioural strategies most strongly associated with rehabilitation response. Cognitive impairment and obesity-related immune regulation further contributed to patient heterogeneity. These observations suggest that rehabilitation responsiveness reflects the interaction of genomic, immune, behavioural and lifestyle factors. Their integration may improve patient stratification and support the development of precision pulmonary rehabilitation.