A systematic review of the diagnostic accuracy of volatile organic compounds in airway diseases and their relation to markers of type-2 inflammation.

Background: Asthma and COPD continue to cause considerable diagnostic and treatment stratification challenges. Volatile organic compounds (VOCs) have been proposed as feasible diagnostic and monitoring biomarkers in airway diseases.

Aims: To 1) conduct a systematic review evaluating the diagnostic accuracy of VOCs in diagnosing airway diseases; 2) understand the relationship between reported VOCs and biomarkers of type-2 inflammation; 3) assess the standardisation of reporting according to STARD and TRIPOD criteria; 4) review current methods of breath sampling and analysis.

Methods: A PRISMA-oriented systematic search was conducted (January 1997 to December 2020). Search terms included: "asthma", "volatile organic compound(s)", "VOC" and "COPD". Two independent reviewers examined the extracted titles against review objectives.

Results: 44 full-text papers were included; 40/44 studies were cross-sectional and four studies were interventional in design; 17/44 studies used sensor-array technologies ( eNose). Cross-study comparison was not possible across identified studies due to the heterogeneity in design. The commonest airway diseases differentiating VOCs belonged to carbonyl-containing classes ( aldehydes, esters and ketones) and hydrocarbons ( alkanes and alkenes). Although individual markers that are associated with clinical biomarkers of type-2 inflammation were recognised ( ethane and 3,7-dimethylnonane for asthma and α-methylstyrene and decane for COPD), these were not consistently identified across studies. Only 3/44 reported following STARD or TRIPOD criteria for diagnostic accuracy and multivariate reporting, respectively.

Conclusions: Breath VOCs show promise as diagnostic biomarkers of airway diseases and for type-2 inflammation profiling. However, future studies should focus on transparent reporting of diagnostic accuracy and multivariate models and continue to focus on chemical identification of volatile metabolites.