Breath gas analysis

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Breath gas analysis
Medical diagnostics
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]

History

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]

[math]\displaystyle{ C_A = \frac{C_{\bar v}}{\lambda_\text{b:air} + \dot V_A/\dot Q_c}, }[/math]

where [math]\displaystyle{ C_A }[/math] 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 [math]\displaystyle{ C_{\bar v} }[/math], the substance-specific blood:air partition coefficient [math]\displaystyle{ \lambda_\text{b:air} }[/math], and the ventilation-perfusion ratio [math]\displaystyle{ \dot V_A/\dot Q_c }[/math]. But this model fails when two prototypical substances like acetone (partition coefficient [math]\displaystyle{ \lambda_\text{b:air} = 340 }[/math]) or isoprene (partition coefficient [math]\displaystyle{ \lambda_\text{b:air} = 0.75 }[/math] ) are measured.[17]

E.g., multiplying the proposed population mean of approximately [math]\displaystyle{ 1 \mu g/L }[/math] acetone in end-tidal breath by the partition coefficient [math]\displaystyle{ \lambda_\text{b:air} = 340 }[/math] at body temperature grossly underestimates observed (arterial) blood levels spreading around [math]\displaystyle{ 1 mg/L }[/math]. 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:

  • Coated stainless steel canister
  • End tidal air collector
  • Tedlar bag

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.

  • Gas chromatography-mass spectrometry GC-MS
  • Gas chromatography-UV spectrometry GC-UV
  • Proton transfer reaction mass spectrometry PTR-MS and PTR-TOF
  • Selected ion flow tube mass spectrometry SIFT-MS
  • Ion mobility spectrometry IMS
  • Fourier transform infrared spectroscopy FTIR
  • Laser spectrometry Spectroscopy
  • Individual Chemical sensors or chemical sensor arrays, operate as Electronic noses
  • Secondary electrospray ionization SESI-MS

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. 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. PMID 31243094. 
  4. ↑ "Inzet SpiroNose stappen dichterbij gekomen". Feb 26, 2020. https://www.longfonds.nl/inzet-spironose-stappen-dichterbij-gekomen. Retrieved 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. doi:10.3978/j.issn.2072-1439.2013.08.44. ISSN 2077-6624. PMID 24163746. 
  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. doi:10.1073/pnas.68.10.2374. ISSN 0027-8424. PMID 5289873. Bibcode: 1971PNAS...68.2374P. 
  7. ↑ Phillips, Michael; Gleeson, Kevin; Hughes, J Michael B; Greenberg, Joel; Cataneo, Renee N; Baker, Leigh; McVay, W Patrick (1999). "Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study". The Lancet 353 (9168): 1930–1933. doi:10.1016/S0140-6736(98)07552-7. PMID 10371572. 
  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. doi:10.1088/1752-7163/ab0bee. ISSN 1752-7163. PMID 30822771. Bibcode: 2019JBR....13c4002A. https://discovery.ucl.ac.uk/id/eprint/10069340/. 
  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. 
  10. ↑ Schallschmidt, Kristin; Becker, Roland; Jung, Christian; Bremser, Wolfram; Walles, Thorsten; Neudecker, Jens; Leschber, Gunda; Frese, Steffen et al. (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. doi:10.1088/1752-7155/10/4/046007. ISSN 1752-7163. PMID 27732569. Bibcode: 2016JBR....10d6007S. [yes|permanent dead link|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. PMID 24957037. 
  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. doi:10.1001/jamaoncol.2018.2815. ISSN 2374-2437. PMID 30128487. 
  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. (October 2015). "Integration of electronic nose technology with spirometry: validation of a new approach for exhaled breath analysis" (in en). Journal of Breath Research 9 (4): 046001. doi:10.1088/1752-7155/9/4/046001. ISSN 1752-7163. PMID 26469298. Bibcode: 2015JBR.....9d6001D. 
  14. ↑ Vries, Rianne de; Dagelet, Yennece W. F.; Spoor, Pien; Snoey, Erik; Jak, Patrick M. C.; Brinkman, Paul; Dijkers, Erica; Bootsma, Simon K. et al. (1 January 2018). "Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label" (in en). European Respiratory Journal 51 (1). doi:10.1183/13993003.01817-2017. ISSN 0903-1936. PMID 29326334. https://erj.ersjournals.com/content/51/1/1701817. 
  15. ↑ https://www.ed.ac.uk/files/atoms/files/easl_posters_rs_0.pdf[bare URL PDF]
  16. ↑ 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) [1]
  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, [2]
  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, [3]
  20. ↑ Farraia, Mariana; Rufo, João Cavaleiro; Paciência, Inês; Mendes, Francisca Castro; Rodolfo, Ana; Rama, Tiago; Rocha, Sílvia M.; Delgado, Luís et al. (July 2020). "Human volatilome analysis using eNose to assess uncontrolled asthma in a clinical setting". Allergy (United States: Wiley) 75 (7): 1630–1639. doi:10.1111/all.14207. ISSN 1398-9995. PMID 31997360. https://www.sensigent.com/img/pdf/2020%20Farraia%20et%20al%20Allergy%20-%20Human%20volatilome%20analysis%20using%20eNose%20to%20assess%20uncontrolled%20asthma%20in%20a%20clinical%20setting.pdf. 
  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. ↑ NASA's electronic nose could sniff out cancer, New Scientist, 27 Aug. 2008.
  24. ↑ Heaney, Liam M.; Ruszkiewicz, Dorota M.; Arthur, Kayleigh L.; Hadjithekli, Andria; Aldcroft, Clive; Lindley, Martin R.; Thomas, CL Paul; Turner, Matthew A. et al. (2016). "Real-time monitoring of exhaled volatiles using atmospheric pressure chemical ionization on a compact mass spectrometer". Bioanalysis 8 (13): 1325–1336. doi:10.4155/bio-2016-0045. PMID 27277875. https://dspace.lboro.ac.uk/2134/22012. 
  25. ↑ Heaney, Liam M.; Lindley, Martin R. (2017). "Translation of exhaled breath volatile analyses to sport and exercise applications". Metabolomics 13 (11). doi:10.1007/s11306-017-1266-z. https://dspace.lboro.ac.uk/2134/27704. 
  26. ↑ 26.0 26.1 Bruderer, Tobias; Gaisl, Thomas; Gaugg, Martin T.; Nowak, Nora; Streckenbach, Bettina; Müller, Simona; Moeller, Alexander; Kohler, Malcolm et al. (2019-10-09). "On-Line Analysis of Exhaled Breath: Focus Review" (in en). Chemical Reviews 119 (19): 10803–10828. doi:10.1021/acs.chemrev.9b00005. ISSN 0009-2665. PMID 31594311. 
  27. ↑ "Fossiliontech - Breath Analysis". https://www.fossiliontech.com/breath-analysis. 
  28. ↑ Singh, Kapil Dev; Tancev, Georgi; Decrue, Fabienne; Usemann, Jakob; Appenzeller, Rhea; Barreiro, Pedro; Jaumà, Gabriel; Macia Santiago, Miriam et al. (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. doi:10.1007/s00216-019-01764-8. ISSN 1618-2650. PMID 30989265. 

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