Breath analysis is a young field of research with its roots in antiquity. Antoine Lavoisier discovered carbon dioxide in exhaled breath during the period 1777-1783, Wilhelm (Vilem) Petters discovered acetone in breath in 1857 and Johannes Muller reported the first quantitative measurements of acetone in 1898. A recent review reported 1765 volatile compounds appearing in exhaled breath, skin emanations, urine, saliva, human breast milk, blood and feces. For a large number of compounds, real-time analysis of exhaled breath or skin emanations has been performed, e.g., during exertion of effort on a stationary bicycle or during sleep. Volatile compounds in exhaled breath, which record historical exposure, are called the 'exposome'. Changes in biogenic volatile organic compound concentrations can be used to mirror metabolic or (patho)physiological processes in the whole body or blood concentrations of drugs (e.g. propofol) in clinical settings-even during artificial ventilation or during surgery. Also compounds released by bacterial strains like Pseudomonas aeruginosa or Streptococcus pneumonia could be very interesting. Methyl methacrylate (CAS 80-62-6), for example, was observed in the headspace of Streptococcus pneumonia in concentrations up to 1420 ppb. Fecal volatiles have been implicated in differentiating certain infectious bowel diseases such as Clostridium difficile, Campylobacter, Salmonella and Cholera. They have also been used to differentiate other non-infectious conditions such as irritable bowel syndrome and inflammatory bowel disease. In addition, alterations in urine volatiles have been used to detect urinary tract infections, bladder, prostate and other cancers. Peroxidation of lipids and other biomolecules by reactive oxygen species produce volatile compounds like ethane and 1-pentane. Noninvasive detection and therapeutic monitoring of oxidative stress would be highly desirable in autoimmunological, neurological, inflammatory diseases and cancer, but also during surgery and in intensive care units. The investigation of cell cultures opens up new possibilities for elucidation of the biochemical background of volatile compounds. In future studies, combined investigations of a particular compound with regard to human matrices such as breath, urine, saliva and cell culture investigations will lead to novel scientific progress in the field.

https://iopscience.iop.org/article/10.1088/1752-7155/8/3/034001/pdf

The human volatilome: volatile organic compounds (VOCs) in exhaled breath, skin emanations, urine, feces and saliva

A new non-invasive and potentially inexpensive frontier in the diagnosis of cancer relies on the detection of volatile organic compounds (VOCs) in exhaled breath samples. Breath can be sampled and analyzed in real-time, leading to fascinating and cost-effective clinical diagnostic procedures. Nevertheless, breath analysis is a very young field of research and faces challenges, mainly because the biochemical mechanisms behind the cancer-related VOCs are largely unknown. In this review, we present a list of 115 validated cancer-related VOCs published in the literature during the past decade, and classify them with respect to their “fat-to-blood” and “blood-to-air” partition coefficients. These partition coefficients provide an estimation of the relative concentrations of VOCs in alveolar breath, in blood and in the fat compartments of the human body. Additionally, we try to clarify controversial issues concerning possible experimental malpractice in the field, and propose ways to translate the basic science results as well as the mechanistic understanding to tools (sensors) that could serve as point-of-care diagnostics of cancer. We end this review with a conclusion and a future perspective.

Assessment, origin, and implementation of breath volatile cancer markers

The analysis of volatile organic compounds in exhaled breath samples represents a new frontier in medical diagnostics because it is a noninvasive and potentially inexpensive way to detect illnesses. Clinical trials with spectrometry and spectroscopy techniques, the standard volatile-compound detection methods, have shown the potential for diagnosing illnesses including cancer, multiple sclerosis, Parkinson’s disease, tuberculosis, diabetes, and more via breath tests. Unfortunately, this approach requires expensive equipment and high levels of expertise to operate the necessary instruments, and the tests must be done quickly and use preconcentration techniques, all of which impede its adoption.Sensing matrices based on nanomaterials are likely to become a clinical and laboratory diagnostic tool because they are significantly smaller, easier-to-use, and less expensive than spectrometry or spectroscopy. An ideal nanomaterial-based sensor for breath testing should be sensitive at very low concentrations of vo...

Sensors for Breath Testing: From Nanomaterials to Comprehensive Disease Detection

Ideally, invading bacteria are detected as early as possible in critically ill patients: the strain of morbific pathogens is identified rapidly, and antimicrobial sensitivity is known well before the start of new antimicrobial therapy. Bacteria have a distinct metabolism, part of which results in the production of bacteria-specific volatile organic compounds (VOCs), which might be used for diagnostic purposes. Volatile metabolites can be investigated directly in exhaled air, allowing for noninvasive monitoring. The aim of this review is to provide an overview of VOCs produced by the six most abundant and pathogenic bacteria in sepsis, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Such VOCs could be used as biological markers in the diagnostic approach of critically ill patients. A systematic review of existing literature revealed 31 articles. All six bacteria of interest produce isopentanol, formaldehyde, methyl mercaptan, and trimethylamine. Since humans do not produce these VOCs, they could serve as biological markers for presence of these pathogens. The following volatile biomarkers were found for identification of specific strains: isovaleric acid and 2-methyl-butanal for Staphylococcus aureus; 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 4-methyl-quinazoline, hydrogen cyanide, and methyl thiocyanide for Pseudomonas aeruginosa; and methanol, pentanol, ethyl acetate, and indole for Escherichia coli. Notably, several factors that may effect VOC production were not controlled for, including used culture media, bacterial growth phase, and genomic variation within bacterial strains. In conclusion, VOCs produced by bacteria may serve as biological markers for their presence. Goal-targeted studies should be performed to identify potential sets of volatile biological markers and evaluate the diagnostic accuracy of these markers in critically ill patients.

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Volatile Metabolites of Pathogens: A Systematic Review

Nanomaterial-based sensors for detection of disease by volatile organic compounds.

Exhaled breath contains thousands of volatile organic compounds (VOCs) of which the composition varies depending on health status. Various metabolic processes within the body produce volatile products that are released into the blood and will be passed on to the airway once the blood reaches the lungs. Moreover, the occurrence of chronic inflammation and/or oxidative stress can result in the excretion of volatile compounds that generate unique VOC patterns. Consequently, measuring the total amount of VOCs in exhaled air, a kind of metabolomics also referred to as breathomics, for clinical diagnosis and monitoring purposes gained increased interest over the last years. This paper describes the currently available methodologies regarding sampling, sample analysis and data processing as well as their advantages and potential drawbacks. Additionally, different application possibilities of VOC profiling are discussed. Until now, breathomics has merely been applied for diagnostic purposes. Exhaled air analysis can, however, also be applied as an analytical or monitoring tool. Within the analytic perspective, the use of VOCs as biomarkers of oxidative stress, inflammation or carcinogenesis is described. As monitoring tool, breathomics can be applied to elucidate the heterogeneity observed in chronic diseases, to study the pathogen(s) responsible for occurring infections and to monitor treatment efficacy.

Emile F Wouters

Papers

The versatile use of exhaled volatile organic compounds in human health and disease