Metabolic effects following initiation of single-inhaler triple therapy in COPD: a prospective observational study

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, airway inflammation, and oxidative stress. Triple inhaled therapy improves lung function and reduces acute exacerbations, yet its underlying systemic effects remain poorly understood. Exhaled breath analysis offers a non-invasive approach to assessing treatment-related metabolic changes. The objective of this study was to characterize the metabolic changes associated with the initiation of single-inhaler triple therapy in COPD patients through real-time mass spectrometry of exhaled breath. In this prospective observational study, patients with COPD were assessed before initiation and after at least 8 weeks of single-inhaler triple therapy. Clinical data, spirometry, symptom scores, and inflammatory markers were collected. Exhaled breath was collected and analyzed by secondary electrospray ionization high-resolution mass spectrometry, and changes in metabolic profiles were evaluated using paired statistics, dimensionality reduction, and pathway enrichment analysis. Twenty-four patients with COPD (mean (standard deviation) age 65 (7) years, 42% female, median (quartiles) forced expiratory volume in the first second (FEV1) 41 (30, 57) % predicted) completed both visits. Breath analysis revealed significantly altered breath features after initiation of single-inhaler triple therapy, with a total of 40 breath features showing both a relevant effect size (|log2 fold change|≥ 1) and statistical evidence (q < 0.22) for within-subject change. Pathway enrichment analysis suggested predominant changes in lipid peroxidation and β-oxidation associated pathways, consistent with altered lipid catabolism and increased oxidative processes. Additionally, breath signatures strongly correlated with fractional exhaled nitric oxide (r = –0.8) and high-sensitivity C-reactive protein (r = –0.93). Predominant molecular changes following initiation of single-inhaler triple therapy were associated with coordinated shifts in breath metabolites consistent with modulation of inflammatory- and oxidative stress-related pathways, suggesting a potential trade-off between anti-inflammatory effects and oxidative processes. ClinicalTrials.gov (NCT05458934).