Exhaled breath volatile organic compounds in cystic fibrosis: a systematic review

Cystic fibrosis (CF) is a genetic disorder characterized by chronic airway infection and progressive lung damage. Early identification of biomarkers associated with respiratory pathogens and inflammatory processes is crucial for improving disease monitoring and guiding therapy. Analysis of volatile organic compounds (VOCs) in exhaled breath has emerged as a promising non-invasive approach for biomarker discovery. Objective: This systematic review aimed to identify and summarize VOCs detected in the exhaled breath of patients with cystic fibrosis that may serve as potential clinical biomarkers. Methods: A systematic literature search was conducted in accordance with PRISMA guidelines across MEDLINE, Web of Science, SCOPUS, and Google Scholar, covering publications from 2000 to 2026. Studies comparing VOC profiles in patients with cystic fibrosis and control groups were included. The risk of bias in the included studies was assessed using the Newcastle-Ottawa Scale. Results: Out of 431 identified records, 27 studies met the inclusion criteria and were included in the qualitative synthesis. These studies employed a variety of analytical platforms, including gas chromatography-mass spectrometry (GC-MS), selected-ion flow-tube mass spectrometry (SIFT-MS), proton transfer reaction mass spectrometry (PTR-MS), and nuclear magnetic resonance (NMR) metabolomics. Across all studies, a total of 121 VOCs were reported in association with cystic fibrosis. Several compounds, including hydrogen cyanide, 2-aminoacetophenone, pentane, and dimethyl sulfide, were repeatedly identified and may represent potential biomarkers related to bacterial colonization, oxidative stress, and inflammatory processes. However, substantial heterogeneity was observed among studies with respect to study design, patient populations, breath sampling protocols, and analytical methodologies. Conclusion: Breath analysis based on volatile organic compounds represents a promising non-invasive approach for identifying biomarkers of cystic fibrosis and associated respiratory infections. Nevertheless, future progress in breathomics will primarily depend on improving methodological rigor rather than limiting the diversity of analytical platforms. Standardized breath sampling protocols, rigorous preprocessing workflows for mass spectrometry data, sufficiently powered multicenter studies, and external validation in independent patient cohorts are essential prerequisites for the clinical implementation of breath-based biomarkers.