Breath gas analysis

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Breath gas analysis
Purposegaining information on the clinical state of an individual by monitoring volatile organic compounds present in the exhaled breath

Breath gas analysis is a method for gaining information on the clinical state of an individual by monitoring volatile organic compounds (VOCs) present in the exhaled breath. Exhaled breath is naturally produced by the human body through expiration and therefore can be collected in non-invasively and in an unlimited way. [1] VOCs in exhaled breath can represent biomarkers for certain pathologies (lung cancer, asthma, chronic obstructive pulmonary disease and others). Breath gas concentration can then be related to blood concentrations via mathematical modeling as for example in blood alcohol testing. [2] There are various techniques that can be employed to collect and analyze exhaled breath. Research on exhaled breath started many years ago, there is currently limited clinical application of it for disease diagnosis. [3] However, this might change in the near future as currently large implementation studies are starting globally. [4]

Contents

History

Lavoiser in his laboratory studying human respiration. 'Lavoisier experimenting in his laboratory Wellcome M0004489.jpg
Lavoiser in his laboratory studying human respiration.

It is known that since the times of Hippocrates, exhaled breath analysis was performed with the aim of disease diagnosis. For example, it was believed that the exhaled breath of a diabetes person presented a sweet odor, while for people affected by kidney failure it showed a fish-like smell. [5] Only with Antonie Lavoisier, the pure smelling of human exhaled breath was substituted by a systematic analysis of the chemical contents. The area of modern breath testing started in 1971, when Nobel Prize winner Linus Pauling demonstrated that human breath is a complex gas, containing more than 200 different VOCs. [6] Later, more than 3000 VOCs have been identified in exhaled breath. [7] In recent years, many scientists have focused on the analysis of exhaled breath with the aim of identifying disease-specific biomarkers at early stages. Lung cancer, [8] COPD and head and neck cancer [9] are among the diseases that have been considered for biomarker detection. Even though exhaled breath analysis started many years ago, there is still no clinical application of it for disease diagnosis. This is mainly due to a lack of standardization of the clinical tests, both for breath collection procedures and their analysis. [10] [11] [12] Though the use of so-called breath-prints, determined by electronic noses, are promising and seem to be able to distinguish between lung cancer, COPD, and asthma. [13] They also seem capable of detecting the various phenotypes of asthma and COPD [14] and other diseases [15]

Overview

Endogenous volatile organic compounds (VOCs) are released within the human organism as a result of normal metabolic activity or due to pathological disorders. They enter the blood stream and are eventually metabolized or excreted via exhalation, skin emission, urine, etc.

Identification and quantification of potential disease biomarkers can be seen as the driving force for the analysis of exhaled breath. Moreover, future applications for medical diagnosis and therapy control with dynamic assessments of normal physiological function or pharmacodynamics are intended.

Exogenous VOCs penetrating the body as a result of environmental exposure can be used to quantify body burden. Also breath tests are often based on the ingestion of isotopically labeled precursors, producing isotopically labeled carbon dioxide and potentially many other metabolites.

However, breath sampling is far from being a standardized procedure due to the numerous confounding factors biasing the concentrations of volatiles in breath. These factors are related to both the breath sampling protocols as well as the complex physiological mechanisms underlying pulmonary gas exchange. Even under resting conditions exhaled breath concentrations of VOCs can be strongly influenced by specific physiological parameters such as cardiac output and breathing patterns, depending on the physico-chemical properties of the compound under study.

Understanding the influence of all the factors and their control is necessary for achieving an accurate standardization of breath sample collection and for the correct deduction of the corresponding blood concentration levels.

The simplest model relating breath gas concentration to blood concentrations was developed by Farhi [16]

where denotes the alveolar concentration which is assumed to be equal to the measured concentration. It expresses the fact that the concentration of an inert gas in the alveolar air depends on the mixed venous concentration , the substance-specific blood:air partition coefficient , and the ventilation-perfusion ratio . But this model fails when two prototypical substances like acetone (partition coefficient ) or isoprene (partition coefficient ) are measured. [17]

E.g., multiplying the proposed population mean of approximately acetone in end-tidal breath by the partition coefficient at body temperature grossly underestimates observed (arterial) blood levels spreading around . Furthermore, breath profiles of acetone (and other highly soluble volatile compounds such as 2-pentanone or methyl acetate) associated with moderate workload ergometer challenges of normal healthy volunteers drastically depart from the trend suggested by the equation above; hence some more refined models are necessary. Such models have been developed. [18] [19]

Applications

Breath gas analysis is used in a number of breath tests.

Breath collectors

Breath can be collected using a variety of home-made and commercially available devices. Some examples of breath collection tools used across the research industry for VOC analysis are:

These devices can be used as a vehicle for direct introduction of a gas sample into an appropriate analytical instrument, or serve as a reservoir of breath gas into which an absorption device such as an SPME fiber is placed to collect specific compounds.

Online analysis

Breath can also be analyzed online, which allows for insight into a person's metabolism without the need for sample preparation or sample collection. [26] Technologies that enable real-time analysis of breath include:

Breath analysis is very vulnerable to confounding factors. Analyzing breath in real-time has the advantage that potential confounding factors associated with sample handling and manipulation are eliminated. Recent efforts have focused on standardizing online breath analysis procedures based on SESI-MS, and to systematically study and reduce other confounding sources of variability. [28]

Analytical instruments

Breath analysis can be done with various forms of mass spectrometry, but there are also simpler methods for specific purposes, such as the Halimeter and the breathalyzer.

Related Research Articles

Dead space is the volume of air that is inhaled that does not take part in the gas exchange, because it either remains in the conducting airways or reaches alveoli that are not perfused or poorly perfused. It means that not all the air in each breath is available for the exchange of oxygen and carbon dioxide. Mammals breathe in and out of their lungs, wasting that part of the inhalation which remains in the conducting airways where no gas exchange can occur.

Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a mass spectrum, a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used in many different fields and is applied to pure samples as well as complex mixtures.

Exhalation is the flow of the breath out of an organism. In animals, it is the movement of air from the lungs out of the airways, to the external environment during breathing. This happens due to elastic properties of the lungs, as well as the internal intercostal muscles which lower the rib cage and decrease thoracic volume. As the thoracic diaphragm relaxes during exhalation it causes the tissue it has depressed to rise superiorly and put pressure on the lungs to expel the air. During forced exhalation, as when blowing out a candle, expiratory muscles including the abdominal muscles and internal intercostal muscles generate abdominal and thoracic pressure, which forces air out of the lungs.

<span class="mw-page-title-main">Gas chromatography–mass spectrometry</span> Analytical method

Gas chromatography–mass spectrometry (GC–MS) is an analytical method that combines the features of gas-chromatography and mass spectrometry to identify different substances within a test sample. Applications of GC–MS include drug detection, fire investigation, environmental analysis, explosives investigation, food and flavor analysis, and identification of unknown samples, including that of material samples obtained from planet Mars during probe missions as early as the 1970s. GC–MS can also be used in airport security to detect substances in luggage or on human beings. Additionally, it can identify trace elements in materials that were previously thought to have disintegrated beyond identification. Like liquid chromatography–mass spectrometry, it allows analysis and detection even of tiny amounts of a substance.

Volatile organic compounds (VOCs) are organic compounds that have a high vapor pressure at room temperature. High vapor pressure correlates with a low boiling point, which relates to the number of the sample's molecules in the surrounding air, a trait known as volatility.

<span class="mw-page-title-main">Selected-ion flow-tube mass spectrometry</span>

Selected-ion flow-tube mass spectrometry (SIFT-MS) is a quantitative mass spectrometry technique for trace gas analysis which involves the chemical ionization of trace volatile compounds by selected positive precursor ions during a well-defined time period along a flow tube. Absolute concentrations of trace compounds present in air, breath or the headspace of bottled liquid samples can be calculated in real time from the ratio of the precursor and product ion signal ratios, without the need for sample preparation or calibration with standard mixtures. The detection limit of commercially available SIFT-MS instruments extends to the single digit pptv range.

<span class="mw-page-title-main">Flowing-afterglow mass spectrometry</span>

Flowing-afterglow mass spectrometry (FA-MS), is an analytical chemistry technique for the sensitive detection of trace gases. Trace gas molecules are ionized by the production and flow of thermalized hydrated hydronium cluster ions in a plasma afterglow of helium or argon carrier gas along a flow tube following the introduction of a humid air sample. These ions react in multiple collisions with water molecules, their isotopic compositions reach equilibrium and the relative magnitudes of their isotopomers are measured by mass spectrometry.

<span class="mw-page-title-main">Electronic nose</span> Electronic sensor for odor detection

An electronic nose is an electronic sensing device intended to detect odors or flavors. The expression "electronic sensing" refers to the capability of reproducing human senses using sensor arrays and pattern recognition systems.

<span class="mw-page-title-main">Proton-transfer-reaction mass spectrometry</span>

Proton-transfer-reaction mass spectrometry (PTR-MS) is an analytical chemistry technique that uses gas phase hydronium reagent ions which are produced in an ion source. PTR-MS is used for online monitoring of volatile organic compounds (VOCs) in ambient air and was developed in 1995 by scientists at the Institut für Ionenphysik at the Leopold-Franzens University in Innsbruck, Austria. A PTR-MS instrument consists of an ion source that is directly connected to a drift tube and an analyzing system. Commercially available PTR-MS instruments have a response time of about 100 ms and reach a detection limit in the single digit pptv or even ppqv region. Established fields of application are environmental research, food and flavor science, biological research, medicine, security, cleanroom monitoring, etc.

Exhaled breath analysis is a method in medicine for gaining information on the clinical state of an individual by monitoring the components present in the exhaled breath.

<span class="mw-page-title-main">Breathing</span> Process of moving air in and out of the lungs

Breathing is the process of moving air into and from the lungs to facilitate gas exchange with the internal environment, mostly to flush out carbon dioxide and bring in oxygen.

Exhaled breath condensate (EBC) is the exhalate from breath, that has been condensed, typically via cooling using a collection device. EBC reflects changes in the respiratory fluid that lines the airways and is an inexpensive, non-invasive tool that has potential for scientific research. Despite its promises, it has not been proven for screening or diagnosing diseases of the lung and other conditions, yet. It has long been appreciated that the exhaled breath is saturated by water vapour, but using it for studies of the lung was probably first described in the Russian scientific literature.

Anton Amann was an Austrian chemist and Professor of chemistry at the Innsbruck Medical University. He worked in the area of physical chemistry, ECG analysis, and exhaled breath analysis.

Breath diagnostics involves the analysis of a sample of human breath to monitor, diagnose, and detect diseases and conditions. Besides its primary constituents – nitrogen, oxygen, carbon dioxide and water vapour – exhaled human breath contains over one thousand other compounds at trace levels. Many of these species are formed as the by-products of metabolic processes and can be indicative of a number of different diseases and conditions. Examples of such biomarkers are outlined below:

Analytical thermal desorption, known within the analytical chemistry community simply as "thermal desorption" (TD), is a technique that concentrates volatile organic compounds (VOCs) in gas streams prior to injection into a gas chromatograph (GC). It can be used to lower the detection limits of GC methods, and can improve chromatographic performance by reducing peak widths.

Volatolomics is a branch of chemistry that studies volatile organic compounds (VOCs) emitted by a biological system, under specific experimental conditions.

The volatilome contains all of the volatile metabolites as well as other volatile organic and inorganic compounds that originate from an organism, super-organism, or ecosystem. The atmosphere of a living planet could be regarded as its volatilome. While all volatile metabolites in the volatilome can be thought of as a subset of the metabolome, the volatilome also contains exogenously derived compounds that do not derive from metabolic processes, therefore the volatilome can be regarded as a distinct entity from the metabolome. The volatilome is a component of the 'aura' of molecules and microbes that surrounds all organisms.

<span class="mw-page-title-main">Secondary electrospray ionization</span>

Secondary electro-spray ionization (SESI) is an ambient ionization technique for the analysis of trace concentrations of vapors, where a nano-electrospray produces charging agents that collide with the analyte molecules directly in gas-phase. In the subsequent reaction, the charge is transferred and vapors get ionized, most molecules get protonated and deprotonated. SESI works in combination with mass spectrometry or ion-mobility spectrometry.

<span class="mw-page-title-main">Coronavirus breathalyzer</span> Diagnostic medical device

A coronavirus breathalyzer is a diagnostic medical device enabling the user to test with 90% or greater accuracy the presence of severe acute respiratory syndrome coronavirus 2 in an exhaled breath. As of the first half of 2020, the idea of a practical coronavirus breathalyzer was concomitantly developed by unrelated research groups in Australia, Canada, Finland, Germany, Indonesia, Israel, Netherlands, Poland, Singapore, United Kingdom and USA.

Smell as evidence of disease has been long used, dating back to Hippocrates around 400 years BCE. It is still employed with a focus on volatile organic compounds (VOCs) found in body odor. VOCs are carbon-based molecular groups having a low molecular weight, secreted during cells’ metabolic processes. Their profiles may be altered by diseases such as cancer, metabolic disorders, genetic disorders, infections, and among others. Abnormal changes in VOC composition can be identified through equipment such as gas chromatography-mass spectrometry(GC-MS), electronic nose (e-noses), and trained non-human olfaction.

References

  1. ↑ Lawal, Oluwasola; Ahmed, Waqar M.; Nijsen, Tamara M. E.; Goodacre, Royston; Fowler, Stephen J. (October 2017). "Exhaled breath analysis: a review of 'breath-taking' methods for off-line analysis". Metabolomics. 13 (10): 110. doi:10.1007/s11306-017-1241-8. ISSN   1573-3882. PMC   5563344 . PMID   28867989.
  2. ↑ Farhi, L.E. (1967). "Elimination of inert gas by the lung". Respiration Physiology. 3 (1): 1–11. doi:10.1016/0034-5687(67)90018-7. PMID   6059100.
  3. ↑ Einoch Amor, Reef; Nakhleh, Morad K.; Barash, Orna; Haick, Hossam (2019-06-30). "Breath analysis of cancer in the present and the future". European Respiratory Review. 28 (152): 190002. doi: 10.1183/16000617.0002-2019 . ISSN   0905-9180. PMC   9489002 . PMID   31243094.
  4. ↑ "Inzet SpiroNose stappen dichterbij gekomen". Longfonds. Feb 26, 2020. Retrieved Aug 14, 2020.
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  6. ↑ Pauling, L.; Robinson, A. B.; Teranishi, R.; Cary, P. (1971-10-01). "Quantitative Analysis of Urine Vapor and Breath by Gas-Liquid Partition Chromatography". Proceedings of the National Academy of Sciences. 68 (10): 2374–2376. Bibcode:1971PNAS...68.2374P. doi: 10.1073/pnas.68.10.2374 . ISSN   0027-8424. PMC   389425 . PMID   5289873.
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  8. ↑ Antoniou, S X; Gaude, E; Ruparel, M; van der Schee, M P; Janes, S M; Rintoul, R C; on behalf of LuCID research group (2019-04-24). "The potential of breath analysis to improve outcome for patients with lung cancer". Journal of Breath Research. 13 (3): 034002. Bibcode:2019JBR....13c4002A. doi:10.1088/1752-7163/ab0bee. ISSN   1752-7163. PMID   30822771. S2CID   73482502.
  9. ↑ Leunis, Nicoline; Boumans, Marie-Louise; Kremer, Bernd; Din, Sinh; Stobberingh, Ellen; Kessels, Alfons G. H.; Kross, Kenneth W. (June 2014). "Application of an electronic nose in the diagnosis of head and neck cancer: Use of an E-Nose in Head and Neck Cancer". The Laryngoscope. 124 (6): 1377–1381. doi:10.1002/lary.24463. PMID   24142627. S2CID   206201540.
  10. ↑ Schallschmidt, Kristin; Becker, Roland; Jung, Christian; Bremser, Wolfram; Walles, Thorsten; Neudecker, Jens; Leschber, Gunda; Frese, Steffen; Nehls, Irene (2016-10-12). "Comparison of volatile organic compounds from lung cancer patients and healthy controls—challenges and limitations of an observational study". Journal of Breath Research. 10 (4): 046007. Bibcode:2016JBR....10d6007S. doi:10.1088/1752-7155/10/4/046007. ISSN   1752-7163. PMID   27732569. S2CID   40896592.[ permanent dead link ]
  11. ↑ Lourenço, Célia; Turner, Claire (2014-06-20). "Breath Analysis in Disease Diagnosis: Methodological Considerations and Applications". Metabolites. 4 (2): 465–498. doi: 10.3390/metabo4020465 . ISSN   2218-1989. PMC   4101517 . PMID   24957037.
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  17. ↑ Julian King, Alexander Kupferthaler, Karl Unterkofler, Helin Koc, Susanne Teschl, Gerald Teschl, Wolfram Miekisch, Jochen Schubert, Hartmann Hinterhuber, and Anton Amann: Isoprene and acetone concentration profiles during exercise at an ergometer, J. Breath Research 3, (2009) 027006 (16 pp)
  18. ↑ Julian King, Helin Koc, Karl Unterkofler, Pawel Mochalski, Alexander Kupferthaler, Gerald Teschl, Susanne Teschl, Hartmann Hinterhuber, and Anton Amann: Physiological modeling of isoprene dynamics in exhaled breath, J. Theoret. Biol. 267 (2010), 626–637,
  19. ↑ Julian King, Karl Unterkofler, Gerald Teschl, Susanne Teschl, Helin Koc, Hartmann Hinterhuber, and Anton Amann: A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone, J. Math. Biol. 63 (2011), 959-999,
  20. ↑ Farraia, Mariana; Rufo, João Cavaleiro; Paciência, Inês; Mendes, Francisca Castro; Rodolfo, Ana; Rama, Tiago; Rocha, Sílvia M.; Delgado, Luís; Brinkman, Paul; Moreira, André (July 2020). "Human volatilome analysis using eNose to assess uncontrolled asthma in a clinical setting" (PDF). Allergy. United States: Wiley. 75 (7): 1630–1639. doi:10.1111/all.14207. ISSN   1398-9995.
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  22. ↑ Tarik Saidi, Omar Zaim, Mohammed Moufid, Nezha El Bari, Radu Ionescu, Benachir Bouchikhi: Exhaled breath analysis using electronic nose and gas chromatography–mass spectrometry for non-invasive diagnosis of chronic kidney disease, diabetes mellitus and healthy subjects, Sensors and Actuators B: Chemical 257 (2018) 178-188.
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