Inhaler Adherence and Biomarkers in COPD: Dynamics between Stable and Exacerbation States

<p dir="ltr">Exacerbation events significantly alter the clinical course of chronic obstructive pulmonary disease (COPD), with patients exhibiting type 2 (T2) inflammation at high risk of frequent exacerbations. Despite the established efficacy of inhaled corticosteroids (ICS) in this group, the impact of inhaler adherence on their inflammatory profile and disease trajectory remains unclear. Conventional management of COPD often overlooks the interplay between adherence and inflammation, and objective inhaler adherence data has been rarely considered in this context.</p><p dir="ltr">This thesis addressed this gap by several projects. Retrospective analyses during and after the COVID-19 pandemic revealed an unexpected shift in the seasonal COPD exacerbation pattern. Moreover, the frequency of exacerbations association with T2 inflammation remained stable, suggesting the concept of a basal exacerbation rate in T2High COPD and highlighting their elevated mortality risk, independent of infective triggers. A systematic review further demonstrated that digital adherence support tools have been scarcely implemented in COPD and no studies had comprehensively linked adherence data to inflammatory biomarker responses.</p><p dir="ltr">To address these shortcomings, a prospective cohort study was conducted, integrating digital adherence monitoring with serial T2 biomarker assessments. Results confirmed a discrepancy between self-reported and objectively measured adherence, with only one-third of participants maintaining optimal adherence (≥75%). Among patients with high T2 inflammation, those with high adherence experienced greater clinical outcomes whereas in non-T2-high patients, increased adherence was paradoxically linked to adverse outcomes. Both blood eosinophils and fractional exhaled nitric oxide emerged as reliable predictors of ICS responsiveness. Additionally, reliever inhaler uses showed as a potential digital biomarker for impending clinical deterioration. The study also identified distinct inflammatory clusters among exacerbations, suggesting heterogeneous treatment responses and the need for tailored therapeutic strategies.</p><p dir="ltr">Overall, this thesis provided a compelling case for biomarker-driven adherence interventions and emphasise the importance of phenotyping COPD as a continuum, from stable to exacerbation stages.</p>