Chest
Volume 147, Issue 1, January 2015, Pages 224-231
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Translating Basic Research Into Clinical Practice
Breathomics in Lung Disease

https://doi.org/10.1378/chest.14-0781Get rights and content

Volatile organic compounds (VOCs) are produced by virtually all metabolic processes of the body. As such, they have potential to serve as noninvasive metabolic biomarkers. Since exhaled VOCs are either derived from the respiratory tract itself or have passed the lungs from the circulation, they are candidate biomarkers in the diagnosis and monitoring of pulmonary diseases in particular. Good examples of the possibilities of exhaled volatiles in pulmonary medicine are provided by the potential use of VOCs to discriminate between patients with lung cancer and healthy control subjects and to noninvasively diagnose infectious diseases and the association between VOCs and markers of disease activity that has been established in obstructive lung diseases. Several steps are, however, required prior to implementation of breath-based diagnostics in daily clinical practice. First, VOCs should be studied in the intention-to-diagnose population, because biomarkers are likely to be affected by multiple (comorbid) conditions. Second, breath collection and analysis procedures need to be standardized to allow pooling of data. Finally, apart from probabilistic analysis for diagnostic purposes, detailed examination of the nature of volatile biomarkers not only will improve our understanding of the pathophysiologic origins of these markers and the nature of potential confounders but also can enable the development of sensors that exhibit maximum sensitivity and specificity toward specific applications. By adhering to such an approach, exhaled biomarkers can be validated in the diagnosis, monitoring, and treatment of patients in pulmonary medicine and contribute to the development of personalized medicine.

Section snippets

VOCs Reflect Metabolism in Humans

VOCs are gaseous organic molecules that are emitted from the fluid phase because they are highly volatile. Human VOCs are released from skin, with feces, urine, and breath and are derived from many metabolic pathways. Since cellular metabolism is altered by disease, the resulting change in VOCs may serve as biomarkers for particular pathophysiologic conditions. In pulmonary medicine, breath is of special interest because of its intensive contact with the respiratory tract. The rate at which

VOC Sampling and Handling

The potential to noninvasively sample breath VOCs is core to the attractiveness of these biomarkers. Depending on the specific application, a variety of techniques to collect exhaled breath are currently available. Progress is made in investigating the influence of these various techniques on exhaled VOCs to provide suggestions for standardization.11, 12, 13 Fortunately, the lack of international guidelines for sampling of VOCs is currently being addressed by task forces. An overview of the

VOC Analysis Techniques

The concepts of the analysis of volatile biomarkers can be understood best by discussing the two ends of the spectrum of available techniques (Fig 2). On one hand, these encompass chemical analytical techniques allowing identification of specific compounds. At the other end of the spectrum are pattern-recognition-based techniques allowing probabilistic dsicrimination of biomarker profiles. It is, however, important to realize that many techniques share features with both of these basic concepts.

Current State of VOC Research and Its Future Potential

The key opportunities and critical challenges for the application of VOCs in clinic are illustrated by the collective experience of their use in three diseases: lung cancer, respiratory infections, and obstructive lung disease.

Challenges and Future Directions

The potential benefits of VOC biomarkers are its noninvasiveness, speed, low costs, and applicability in low-income countries. Much work, however, is needed before VOC-based diagnostic tools meet the criteria in Table 1 and can be implemented, because current progress can only be classified as phase 2 to 4 on the 10-step technology readiness assessment scale.52

A key issue with volatile biomarkers identified to date is the relative absence of independently reproduced biomarkers undermining the

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts: Dr van Aalderen is a member of advisory boards for Astra Zeneca, Teva Pharmaceuticals Ltd, Mundipharma International, and AbbVie Inc. Drs van der Schee, Paff, Haarman, and Sterk and Mr Brinkman report no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

References (63)

  • P Montuschi et al.

    Diagnostic performance of an electronic nose, fractional exhaled nitric oxide, and lung function testing in asthma

    Chest

    (2010)
  • CO Olopade et al.

    Exhaled pentane levels in acute asthma

    Chest

    (1997)
  • S Kischkel et al.

    Breath biomarkers for lung cancer detection and assessment of smoking related effects—confounding variables, influence of normalization and statistical algorithms

    Clin Chim Acta

    (2010)
  • J King et al.

    Physiological modeling of isoprene dynamics in exhaled breath

    J Theor Biol

    (2010)
  • E Aghdassi et al.

    Breath alkanes as a marker of oxidative stress in different clinical conditions

    Free Radic Biol Med

    (2000)
  • WF Bynum et al.
    (1993)
  • DM Dosa

    A day in the life of Oscar the cat

    N Engl J Med

    (2007)
  • A Amann et al.

    Assessment of the exhalation kinetics of volatile cancer biomarkers based on their physicochemical properties

    J Breath Res

    (2014)
  • H Haick et al.

    Assessment, origin, and implementation of breath volatile cancer markers

    Chem Soc Rev

    (2014)
  • L Pauling et al.

    Quantitative analysis of urine vapor and breath by gas-liquid partition chromatography

    Proc Natl Acad Sci U S A

    (1971)
  • CE Wheelock et al.

    U-BIOPRED Study Group Application of 'omics technologies to biomarker discovery in inflammatory lung diseases

    Eur Respir J

    (2013)
  • G Peng et al.

    Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors

    Br J Cancer

    (2010)
  • S Sethi et al.

    Clinical application of volatile organic compound analysis for detecting infectious diseases

    Clin Microbiol Rev

    (2013)
  • RA Stockley

    Biomarkers in COPD: time for a deep breath

    Thorax

    (2007)
  • TY Khalid et al.

    Volatiles from oral anaerobes confounding breath biomarker discovery

    J Breath Res

    (2013)
  • M D'Addario et al.

    A modular computational framework for automated peak extraction from ion mobility spectra

    BMC Bioinformatics

    (2014)
  • A Bikov et al.

    Standardised exhaled breath collection for the measurement of exhaled volatile organic compounds by proton transfer reaction mass spectrometry

    BMC Pulm Med

    (2013)
  • F Röck et al.

    Electronic nose: current status and future trends

    Chem Rev

    (2008)
  • AA Shvartsburg et al.

    Separation of protein conformers by differential ion mobility in hydrogen-rich gases

    Anal Chem

    (2013)
  • C Bushdid et al.

    Humans can discriminate more than 1 trillion olfactory stimuli

    Science

    (2014)
  • AG Dent et al.

    Exhaled breath analysis for lung cancer

    J Thorac Dis

    (2013)
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    Drs van der Schee and Paff are both first authors, contributing equally to this manuscript.

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