Acute COPD exacerbation despite triple inhaled therapy: a molecular insight – TripleEx study

Background: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by persistent airflow limitation and acute exacerbations (AECOPD), which accelerate disease progression. Although triple inhaled therapy is recommended for patients with severe COPD and frequent AECOPD, some patients continue to experience exacerbations. The mechanisms behind this remain unclear. Exhaled breath analysis has the potential to unravel molecular changes during AECOPD, thereby adding to the understanding of molecular drivers for AECOPD. This study aimed to investigate metabolic changes in exhaled breath during AECOPD compared to stable state. Methods: In COPD patients treated with triple inhaled therapy we conducted real time breath analysis during AECOPD and subsequent stable state. Molecular breath patterns were compared between AECOPD and stable state by pathway enrichment analysis. Minimum description length model was used to build a feature based prediction model differentiating AECOPD from stable state. Results: 28 patients (61% male) with a mean (SD) age of 65 (10.2) years with severe AECOPD were included. Metabolic alterations were predominantly detected in aminosugar, linoleate, and butanoate pathways. AECOPD could be discriminated from stable state with high power (AUC = 0.84), and balanced good sensitivity and specificity (86% each). Conclusion: Metabolic analysis of AECOPD revealed disturbances in aminosugar metabolism as a potential driver mechanism and thus may be a therapeutic target for patients with exacerbations despite triple inhaled therapy. Moreover, real-time breath analysis could enable rapid detection of AECOPD, improving diagnostic accuracy and treatment efficiency. Trial registration: ClinicalTrials.gov (NCT04638920), registered on 20.11.2020.