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

Abstract

BackgroundAsthma 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 airways diseases.AimsTo conduct a systematic review evaluating (i) the diagnostic accuracy of VOCs in diagnosing airways diseases, (ii) understand the relationship between reported VOCs and biomarkers of type-2 inflammation, (iii) assess the standardisation of reporting according to STARD and TRIPOD criteria, (iv) review current methods of breath sampling and analysisMethodsA PRISMA-oriented systematic search was conducted (January 1997–December 2020). Search terms included: “asthma”, “volatile organic compound(s)”, “VOC”, and “COPD”. Two independent reviewers examined the extracted titles against review objectives.Results44 full-text papers were included. 40/44 studies were cross-sectional and 4 studies were interventional in design. 17/44 studies used sensor-array technologies (e.g. eNose). Cross-study comparison was not possible across identified studies due to the heterogeneity in design. The commonest airways diseases differentiating VOCs belonged to carbonyl-containing classes (i.e. Aldehydes, Esters, and Ketones) and hydrocarbons (i.e. Alkanes and Alkenes). Although individual markers that are associated with clinical biomarkers of type-2 inflammation were recognised (i.e. 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.ConclusionsBreath VOCs show promise as diagnostic biomarkers of airways 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.

Investigating a structured diagnostic approach for chronic breathlessness in primary care: a mixed-methods feasibility cluster Randomised Controlled Trial

“…Advances are being made with biomarkers other than blood tests; the role of exhaled breath volatile organic compounds in differentiating acute breathlessness has been explored as an option for non-invasive diagnostics in acute settings with cardiorespiratory patients(41). It is not currently known how this could translate into primary care but there is urgent need for novel diagnostics particularly for airways disease.…”

Increased breath naphthalene in children with asthma and wheeze of the All Age Asthma Cohort (ALLIANCE)

“…11 of the compounds found to be different between healthy children and patients (table 2) have been related to asthma in previous studies [13,14], however the overlap with our results is quite small. Recent reviews show that this is not uncommon in studies with asthma or wheezing patients [12,13] and very likely due to differences in patient populations and in sampling and analysis methods. Furthermore, as we used a predefined target VOC dataset comprising of 158 VOCs, we might not have detected some of the previously reported VOCs in comparable trials with asthma patients.…”

“…While exhaled nitric oxide is considered as an established non-invasively accessible biomarker [10,11], it mainly reflects the level of eosinophilic airway inflammation. For a more comprehensive analysis, volatile organic compounds (VOCs) in exhaled breath have gained considerable interest as biomarkers for lung diseases, especially in asthma [12][13][14].…”

“…Breath collection is non-invasive and only requires tidal breathing which makes it particularly attractive for the use in children even at a young age. A number of studies on breath VOCs in adult and pediatric asthma have been published in the last decade and are considered in recent reviews [12][13][14]. For example, Dallinga et al showed that exhaled VOCs can distinguish asthmatic from non-asthmatic children [15], and there is evidence that breath VOCs identify distinct inflammation phenotypes [16] or predict exacerbations in asthmatic children [17,18].…”

Exhaled volatile organic compounds for diagnosis and monitoring of asthma

“…To date, GC-MS is the standard method used for characterizing the human metabolome, including VOCs present in human breath[ 25 , 26 ]. GC-MS can identify low-molecular-weight metabolites containing carbon and link VOCs to possible pathophysiological pathways helping us to better understand the asthmatic disease[ 27 , 28 ].…”