Untargeted Sweat and Sebum Volatilomics by HS-SPME-GC/ToF-MS for the Identification of SARS-CoV-2-Associated...

Background/Objectives: The COVID-19 pandemic has emphasized the urgent need for non-invasive diagnostic strategies. While breath analysis has been widely investigated, sweat and sebum remain largely unexplored, despite being abundant, chemically diverse, and easily collected. This exploratory study presents a proof-of-concept workflow to evaluate their potential for infection biomarker discovery. Methods: Samples from 51 subjects were analyzed by headspace solid-phase microextraction coupled with gas chromatography and time-of-flight mass spectrometry (HS-SPME-GC/ToF-MS). Over 8000 untargeted volatile compounds were detected, reflecting the high complexity of these matrices. Results: Data refinement and chemometric modelling using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) revealed robust separation between SARS-CoV-2-positive Patients and Controls. Classification accuracies consistently exceeded 95%, demonstrating the robust discriminative performance of the approach. Among the detected volatiles, 2-methylbenzenemethanol acetate emerged as the most informative compound, representing a potential biomarker candidate. Conclusions: This work shows that the sweat and sebum volatilome can be exploited for clinical applications. The workflow integrates non-invasive sampling, comprehensive chromatographic profiling, and advanced statistical modelling, representing a methodological contribution to analytical chemistry. Beyond COVID-19, the strategy provides a potential framework for volatile organic compound (VOC)-based diagnostics across different diseases and supports future development of sensor technologies for translation into healthcare practice.