Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review

Abstract

There is an increasing interest in the potential of exhaled biomarkers, such as volatile organic compounds (VOCs), to improve accurate diagnoses and management decisions in pulmonary diseases. The objective of this manuscript is to systematically review the current knowledge on exhaled VOCs with respect to their potential clinical use in asthma, lung cancer, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and respiratory tract infections. A systematic literature search was performed in PubMed, EMBASE, Cochrane database, and reference lists of retrieved studies. Controlled, clinical, English-language studies exploring the diagnostic and monitoring value of VOCs in asthma, COPD, CF, lung cancer and respiratory tract infections were included. Data on study design, setting, participant characteristics, VOCs techniques, and outcome measures were extracted. Seventy-three studies were included, counting in total 3,952 patients and 2,973 healthy controls. The collection and analysis of exhaled VOCs is non-invasive and could be easily applied in the broad range of patients, including subjects with severe disease and children. Various research groups demonstrated that VOCs profiles could accurately distinguish patients with a pulmonary disease from healthy controls. Pulmonary diseases seem to be characterized by a disease specific breath-print, as distinct profiles were found in patients with dissimilar diseases. The heterogeneity of studies challenged the inter-laboratory comparability. In conclusion, profiles of VOCs are potentially able to accurately diagnose various pulmonary diseases. Despite these promising findings, multiple challenges such as further standardization and validation of the diverse techniques need to be mastered before VOCs can be applied into clinical practice.

Figure 1

Techniques to assess airway inflammation and oxidative stress. There are various methods to measure airway inflammation and oxidative stress ranging from completely non-invasive (exhaled breath analysis) to very invasive (open lung biopsy).

Figure 2

Breath-print of VOCs by gas chromatography. With the gas chromatography (GC) technique, exhaled breath is collected and temporarily stored in e.g. gas-tight syringes, glass bulbs, inert bags, or metal containers. Once the VOCs are collected and temporarily trapped, they can be released for analysis. This is often performed by solvent or thermal desorption. Subsequently, the analysis of individual molecular components can be assessed by GC usually followed by mass spectrometry (GC-MS) or flame ionization detection (GC-FID). The diverse VOCs are separated and quantified by using their specific compound characteristics. Distinct VOCs have dissimilar progression rates and reach the end of the GC column at different time points; the retention time. Based on their retention time, VOCs can be identified in a mass-spectra library. The figure demonstrates an example of a chromatogram of a breath sample analyzed with GC. The retention time (in minutes) is stated on the x axis, while the y axis shows the relative abundance of various compound signals. Published in Robroeks et al. Pediatr Res 2010 [14].

Figure 3

Breath-print of VOCs by the electronic Nose. Breath samples can also be analyzed using an eNose. The eNose consists of an array of nanosensors. When these sensors are exposed to a mixture of VOCs, a change in their electrical resistance is induced, leading to the production of a ‘breath-print’. This breath-print represents the complex mixture of exhaled VOCs and can be used for pattern-recognition algorithms in multiple diseases. A limitation of the eNose is that it is unable to analyze individual VOCs. In the figure two exhaled breath-prints analyzed with the eNose are demonstrated (purple line represents sample 1, green line represents sample 2). The y axis represents the change in resistance (Δ R/Rt = 0) of each of the 28 sensors (1–28). Courtesy: Paul Brinkman, Niki Fens, Peter Sterk, University of Amsterdam, the Netherlands.

Figure 4

Flow-chart of literature search. Summary of evidence search and selection according to the Prisma flow-chart [16]. Abbreviations: VOCs = Volatile Organic Compounds.