Recently breath analysis has attracted a lot of attention for disease monitoring and clinical diagnostics as spectrometric techniques of high sophistication and novel sensing materials become ...available. Here advances in these technologies in connection to breath analysis are critically reviewed. A number of breath markers or tracer compounds are summarized and related to different diseases, either for diagnostics or for monitoring. Emphasis is placed on chemo-resistive gas sensors for their low cost and portability highlighting their potential and challenges for breath analysis as they start to be used in studies involving humans.
Hybrid Volatolomics and Disease Detection Broza, Yoav Y.; Mochalski, Pawel; Ruzsanyi, Vera ...
Angewandte Chemie (International ed.),
September 14, 2015, Letnik:
54, Številka:
38
Journal Article
Recenzirano
This Review presents a concise, but not exhaustive, didactic overview of some of the main concepts and approaches related to “volatolomics”—an emerging frontier for fast, risk‐free, and potentially ...inexpensive diagnostics. It attempts to review the source and characteristics of volatolomics through the so‐called volatile organic compounds (VOCs) emanating from cells and their microenvironment. It also reviews the existence of VOCs in several bodily fluids, including the cellular environment, blood, breath, skin, feces, urine, and saliva. Finally, the usefulness of volatolomics for diagnosis from a single bodily fluid, as well as ways to improve these diagnostic aspects by “hybrid” approaches that combine VOC profiles collected from two or more bodily fluids, will be discussed. The perspectives of this approach in developing the field of diagnostics to a new level are highlighted.
Ill‐gotten gains: Volatolomes enable identification of the collection of volatile organic compounds in a biological cell, tissue, or organism that are the by‐/end products of cellular processes in the living organism. The new analytical approach of volatolomics allows the large‐scale scientific study of chemical processes involving volatile organic compounds.
Display omitted
► Portable sensors were developed and tested for monitoring acetone in the human breath. ► Acetone concentrations down to 20ppb were measured with short response times (<30s). ► The ...present sensors were highly selective to acetone over ethanol and water. ► Sensors were applied to human breath: good agreement with highly sensitive PTR-MS. ► Tests with people at rest and during physical activity showed the sensor robustness.
Breath analysis has the potential for early stage detection and monitoring of illnesses to drastically reduce the corresponding medical diagnostic costs and improve the quality of life of patients suffering from chronic illnesses. In particular, the detection of acetone in the human breath is promising for non-invasive diagnosis and painless monitoring of diabetes (no finger pricking). Here, a portable acetone sensor consisting of flame-deposited and in situ annealed, Si-doped epsilon-WO3 nanostructured films was developed. The chamber volume was miniaturized while reaction-limited and transport-limited gas flow rates were identified and sensing temperatures were optimized resulting in a low detection limit of acetone (∼20ppb) with short response (10–15s) and recovery times (35–70s). Furthermore, the sensor signal (response) was robust against variations of the exhaled breath flow rate facilitating application of these sensors at realistic relative humidities (80–90%) as in the human breath. The acetone content in the breath of test persons was monitored continuously and compared to that of state-of-the-art proton transfer reaction mass spectrometry (PTR-MS). Such portable devices can accurately track breath acetone concentration to become an alternative to more elaborate breath analysis techniques.
The routinely used microbiological diagnosis of ventilator associated pneumonia (VAP) is time consuming and often requires invasive methods for collection of human specimens (e.g. bronchoscopy). ...Therefore, it is of utmost interest to develop a non-invasive method for the early detection of bacterial infection in ventilated patients, preferably allowing the identification of the specific pathogens. The present work is an attempt to identify pathogen-derived volatile biomarkers in breath that can be used for early and non- invasive diagnosis of ventilator associated pneumonia (VAP). For this purpose, in vitro experiments with bacteria most frequently found in VAP patients, i.e. Staphylococcus aureus and Pseudomonas aeruginosa, were performed to investigate the release or consumption of volatile organic compounds (VOCs).
Headspace samples were collected and preconcentrated on multibed sorption tubes at different time points and subsequently analyzed with gas chromatography mass spectrometry (GC-MS). As many as 32 and 37 volatile metabolites were released by S. aureus and P. aeruginosa, respectively. Distinct differences in the bacteria-specific VOC profiles were found, especially with regard to aldehydes (e.g. acetaldehyde, 3-methylbutanal), which were taken up only by P. aeruginosa but released by S. aureus. Differences in concentration profiles were also found for acids (e.g. isovaleric acid), ketones (e.g. acetoin, 2-nonanone), hydrocarbons (e.g. 2-butene, 1,10-undecadiene), alcohols (e.g. 2-methyl-1-propanol, 2-butanol), esters (e.g. ethyl formate, methyl 2-methylbutyrate), volatile sulfur compounds (VSCs, e.g. dimethylsulfide) and volatile nitrogen compounds (VNCs, e.g. 3-methylpyrrole).Importantly, a significant VOC release was found already 1.5 hours after culture start, corresponding to cell numbers of ~8*106 CFUs/ml.
The results obtained provide strong evidence that the detection and perhaps even identification of bacteria could be achieved by determination of characteristic volatile metabolites, supporting the clinical use of breath-gas analysis as non-invasive method for early detection of bacterial lung infections.
•Quantification of volatiles emitted by human skin by SPME-GCMS.•Determination of emission rates of 64 skin-borne species.•Selection of potential skin-borne markers of human presence for rescue ...applications.
Gas chromatography with mass spectrometric detection (GC–MS) coupled with solid phase micro-extraction as pre-concentration method (SPME) was applied to identify and quantify volatile organic compounds (VOCs) emitted by human skin. A total of 64 C4-C10 compounds were quantified in skin emanation of 31 healthy volunteers. Amongst them aldehydes and hydrocarbons were the predominant chemical families with eighteen and seventeen species, respectively. Apart from these, there were eight ketones, six heterocyclic compounds, six terpenes, four esters, two alcohols, two volatile sulphur compounds, and one nitrile. The observed median emission rates ranged from 0.55 to 4790fmolcm−2min−1. Within this set of analytes three volatiles; acetone, 6-methyl-5-hepten-2-one, and acetaldehyde exhibited especially high emission rates exceeding 100fmolcm−2min−1. Thirty-three volatiles were highly present in skin emanation with incidence rates over 80%. These species can be considered as potential markers of human presence, which could be used for early location of entrapped victims during Urban Search and Rescue Operations (USaR).
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 (Vilém) Petters discovered ...acetone in breath in 1857 and Johannes Müller 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.
The stability of 41 selected breath constituents in three types of polymer sampling bags, Tedlar, Kynar, and Flexfilm, was investigated using solid phase microextraction and gas chromatography mass ...spectrometry. The tested molecular species belong to different chemical classes (hydrocarbons, ketones, aldehydes, aromatics, sulphurs, esters, terpenes, etc.) and exhibit close-to-breath low ppb levels (3-12 ppb) with the exception of isoprene, acetone and acetonitrile (106 ppb, 760 ppb, 42 ppb respectively). Stability tests comprised the background emission of contaminants, recovery from dry samples, recovery from humid samples (RH 80% at 37 °C), influence of the bag's filling degree, and reusability. Findings yield evidence of the superiority of Tedlar bags over remaining polymers in terms of background emission, species stability (up to 7 days for dry samples), and reusability. Recoveries of species under study suffered from the presence of high amounts of water (losses up to 10%). However, only heavier volatiles, with molecular masses higher than 90, exhibited more pronounced losses (20-40%). The sample size (the degree of bag filling) was found to be one of the most important factors affecting the sample integrity. To sum up, it is recommended to store breath samples in pre-conditioned Tedlar bags up to 6 hours at the maximum possible filling volume. Among the remaining films, Kynar can be considered as an alternative to Tedlar; however, higher losses of compounds should be expected even within the first hours of storage. Due to the high background emission Flexfilm is not suitable for sampling and storage of samples for analyses aiming at volatiles at a low ppb level.
Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, ...non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless.
Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers.
Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS-results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons.
GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important.
PDF
