Breath gas analysis explained

Breath gas analysis
Purpose:gaining 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]

History

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]

CA=

C\bar
λ+
•
V
•
A/Q
c
b:air

,

where

CA

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

C\bar

, the substance-specific blood:air partition coefficient

λb:air

, and the ventilation-perfusion ratio
•
V
•
A/Q

c

.But this model fails when two prototypical substances like acetone (partition coefficient

λb:air=340

) or isoprene (partition coefficient

λb:air=0.75

) are measured.[17]

E.g., multiplying the proposed population mean of approximately

1\mug/L

acetone in end-tidal breath by the partition coefficient

λb:air=340

at body temperature grossly underestimates observed (arterial) blood levels spreading around

1mg/L

. 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.

External links

Notes and 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. 10.1007/s11306-017-1241-8. 28867989. 5563344. 1573-3882.
  2. Farhi. L.E.. Elimination of inert gas by the lung. Respiration Physiology. 3. 1. 1–11. 10.1016/0034-5687(67)90018-7. 6059100. 1967.
  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. 10.1183/16000617.0002-2019. 31243094. 9489002 . 0905-9180. free.
  4. Web site: Inzet SpiroNose stappen dichterbij gekomen. Feb 26, 2020. Longfonds. Aug 14, 2020.
  5. Dent. Annette G.. Sutedja. Tom G.. Zimmerman. Paul V.. 2013-09-26. Exhaled breath analysis for lung cancer. Journal of Thoracic Disease. 5. 5. S540–S550–S550. 10.3978/j.issn.2072-1439.2013.08.44. 24163746. 2077-6624. 3804873.
  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. 10.1073/pnas.68.10.2374. 5289873. 0027-8424. 389425. 1971PNAS...68.2374P. free.
  7. Phillips. Michael. Gleeson. Kevin. Hughes. J Michael B. Greenberg. Joel. Cataneo. Renee N. Baker. Leigh. McVay. W Patrick. Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study. The Lancet. 353. 9168. 1930–1933. 10.1016/S0140-6736(98)07552-7. 10371572. 1999. 6331709.
  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. 73482502. 2019-04-24. The potential of breath analysis to improve outcome for patients with lung cancer. Journal of Breath Research. 13. 3. 034002. 10.1088/1752-7163/ab0bee. 30822771. 2019JBR....13c4002A. 1752-7163.
  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. 10.1002/lary.24463. 24142627. 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. 10.1088/1752-7155/10/4/046007. 27732569. 1752-7163. 2016JBR....10d6007S. 40896592 .
  11. Lourenço. Célia. Turner. Claire. 2014-06-20. Breath Analysis in Disease Diagnosis: Methodological Considerations and Applications. Metabolites. 4. 2. 465–498. 10.3390/metabo4020465. 24957037. 2218-1989. 4101517. free.
  12. Hanna. George B.. Boshier. Piers R.. Markar. Sheraz R.. Romano. Andrea. 2019-01-10. Accuracy and Methodologic Challenges of Volatile Organic Compound–Based Exhaled Breath Tests for Cancer Diagnosis: A Systematic Review and Meta-analysis. JAMA Oncology. 5. 1. e182815. 10.1001/jamaoncol.2018.2815. 30128487. 2374-2437. 6439770.
  13. Vries . R. de . Brinkman . P. . Schee . M. P. van der . Fens . N. . Dijkers . E. . Bootsma . S. K. . Jongh . F. H. C. de . Sterk . P. J. . Integration of electronic nose technology with spirometry: validation of a new approach for exhaled breath analysis . Journal of Breath Research . October 2015 . 9 . 4 . 046001 . 10.1088/1752-7155/9/4/046001 . 26469298 . 2015JBR.....9d6001D . en . 1752-7163. free .
  14. Vries . Rianne de . Dagelet . Yennece W. F. . Spoor . Pien . Snoey . Erik . Jak . Patrick M. C. . Brinkman . Paul . Dijkers . Erica . Bootsma . Simon K. . Elskamp . Fred . Jongh . Frans H. C. de . Haarman . Eric G. . Veen . Johannes C. C. M. in ‘t . Zee . Anke-Hilse Maitland-van der . Sterk . Peter J. . Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label . European Respiratory Journal . 1 January 2018 . 51 . 1 . 10.1183/13993003.01817-2017 . 29326334 . en . 0903-1936. free .
  15. Web site: Electronic-nose breath print distinguishes non-alcoholic fatty liver disease from healthy lean control: a pilot study . R. . Sinha . IJ . Gallagher . KA . Lockman . RAFM . Chamuleau . AJ . Jaap . PC . Hayes . JN . Plevris . The International Liver Conference 2018 . Paris, France . April 11-15, 2018 . Aug 11, 2024.
  16. https://dx.doi.org/10.1016/0034-5687(67)90018-7 Leon E. Farhi: Elimination of inert gas by the lung, Respiration Physiology 3 (1967) 1–11
  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) http://iopscience.iop.org/1752-7163/3/2/027006
  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, https://arxiv.org/abs/1010.2145
  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, https://dx.doi.org/10.1007/s00285-010-0398-9
  20. Farraia. Mariana. Rufo . João Cavaleiro. Paciência . Inês. Mendes. Francisca Castro . Rodolfo. Ana . Rama . Tiago . Rocha. Sílvia M. . Delgado. Luís. Brinkman. Paul . Moreira. André. Human volatilome analysis using eNose to assess uncontrolled asthma in a clinical setting. Allergy. 75. 7. 1630–1639. Wiley. United States. July 2020. 1398-9995. 10.1111/all.14207. 31997360. 210946966.
  21. Michael P. Hlastala: The alcohol breath test—a review, Journal of Applied Physiology (1998) vol. 84 no. 2, 401–408.
  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.
  23. https://www.newscientist.com/channel/tech/mg19926715.200-nasas-electronic-nose-could-sniff-out-cancer.html NASA's electronic nose could sniff out cancer, New Scientist, 27 Aug. 2008.
  24. 10.4155/bio-2016-0045. 27277875. Real-time monitoring of exhaled volatiles using atmospheric pressure chemical ionization on a compact mass spectrometer. Bioanalysis. 8. 13. 1325–1336. 2016. Heaney. Liam M.. Ruszkiewicz. Dorota M.. Arthur. Kayleigh L.. Hadjithekli. Andria. Aldcroft. Clive. Lindley. Martin R.. Thomas. CL Paul. Turner. Matthew A.. Reynolds. James C.. 22817790 .
  25. 10.1007/s11306-017-1266-z. Translation of exhaled breath volatile analyses to sport and exercise applications. Metabolomics. 13. 11. 2017. Heaney. Liam M.. Lindley. Martin R.. 207266001. 2381/40421. free.
  26. Bruderer. Tobias. Gaisl. Thomas. Gaugg. Martin T.. Nowak. Nora. Streckenbach. Bettina. Müller. Simona. Moeller. Alexander. Kohler. Malcolm. Zenobi. Renato. 2019-10-09. On-Line Analysis of Exhaled Breath: Focus Review. Chemical Reviews. en. 119. 19. 10803–10828. 10.1021/acs.chemrev.9b00005. 31594311. 0009-2665. 20.500.11850/372767. 202036999 . free.
  27. Web site: Fossiliontech - Breath Analysis. Fossil Ion Technology - Breath Research Instrumentation. 2019-05-29.
  28. Singh. Kapil Dev. Tancev. Georgi. Decrue. Fabienne. Usemann. Jakob. Appenzeller. Rhea. Barreiro. Pedro. Jaumà. Gabriel. Macia Santiago. Miriam. Vidal de Miguel. Guillermo. 2019-04-15. Standardization procedures for real-time breath analysis by secondary electrospray ionization high-resolution mass spectrometry. Analytical and Bioanalytical Chemistry. 411. 19. 4883–4898. 10.1007/s00216-019-01764-8. 30989265. 6611759. 1618-2650.

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