Review
Pathologies currently identified by exhaled biomarkers

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Abstract

Ancient Greek physicians already knew that the smell of human breath could provide a clue to the pathology. Nowadays, volatile breath biomarkers are known to be released in a broad range of diseases. However, their identification, isolation, and quantification as indicative of relevant alterations in clinical status have required the development of new techniques and analytical methods. Breath sample analysis encounters several obstacles. Particularly, there is a need of a system that could work in a continuous manner, with the low concentration and small volume of a sample. Herein we review, in the light of literature and our experience, clinical applications of the metal oxide semiconductor (MOS) sensor for breath analysis to distinguish between health and disease in some conditions, e.g., diabetes, multiple chemical sensitivity (MCS) syndrome, or in tracing the central neural fatigue resulting from cognitive performance. We submit that exhaled breath analysis holds promise in the diagnosis and treatment of genetic or neurodegenerative diseases which involve cognitive derangements.

Highlights

► Volatile breath markers distinguish health from disease. ► Multiple chemical sensitivity (MCS) syndrome underlies chronic fatigue. ► Electronic nose identifies ‘smellprint’ characteristic of lung cancer. ► Volatile organic compounds (VOCs) change in exhaled breath during cognitive tasks.

Introduction

Biophysical, biochemical, and molecular biological methods have mainly been developed for blood and urine analysis in medical monitoring equipments and diagnostics. Comparatively, diagnostics based on breath analysis, which are among the least invasive methods for monitoring person's health, are less developed and not yet regularly used in clinical practice. The applications of breath tests are valuable in diagnosis of disease, including aging and neurodegenerative pathology, and in the assessment of exposure to environmental pollutants or drugs (Risby and Sehnert, 1999, Cao and Duan, 2006).

Gas exchange at the alveolar-blood capillary membrane of the respiratory tract is essential to life. This mechanism is a passive diffusion driven by the carbon dioxide and oxygen unbalanced concentration gradients. Following these vital gasses, molecules present either in the blood or in inhaled air can also diffuse passively into the breath or blood, respectively. Interestingly, exhaled breath could be characterized by a distinctive smell. These unique stenches have been used, since the time of Hippocrates, as indicators of several diseases: diabetes, lung, liver or renal pathology, sepsis, or periodontal infections (Phillips, 1992). These intuitive observations have later been proven by using classical analytical methods. The molecular profile of breath has been characterized in concentrations and identities of the compounds in healthy and pathological conditions (for review see Miekisch et al., 2004). Principal components up to 99% are few compounds: nitrogen, oxygen, carbon dioxide, water vapor, and the inert gases. The residue consists of a mixture of many molecules with concentrations in the range of parts per million (ppm) to parts per trillion (ppt) by volume (Chen et al., 1970, Pauling et al., 1971, Riely et al., 1974, Dannecker et al., 1981, Solga and Risby, 2010). In normal subjects, more than 3400 different volatile organic compounds (VOCs) can be detected in the exhaled breath; however, only a small fraction of these VOCs are present in all subjects. These are principally isoprene, alkanes, methylalkane, and benzene derivatives (Phillips et al., 1999). Intuitively, this residual part is the most interesting for searching biomarkers of pathological conditions (Risby, 2002). However, given the minute concentration of these molecules, it is essential to investigate breath by the application of new generation of analytical instruments capable of high resolution detection (Risby and Solga, 2006, Solga and Risby, 2010). This review is intended to describe the broad range of applications of breath analysis, including a new sensor generation and its potential for clinical diagnosis of new diseases and a real time monitoring during cognitive performance tests.

Section snippets

Breath analysis techniques, limitations and future perspectives

Capnography is a classic monitoring system of the concentration or partial pressure of carbon dioxide (CO2) in the respiratory gases. It provides information about CO2 production, lung perfusion, alveolar ventilation, respiratory patterns, indirect metabolism measurement, and elimination of CO2 after anesthesia from the breathing circuit and ventilator. It is usually represented as a graph, the capnogram, of expiratory CO2 plotted against time or expired volume. The capnogram is a direct

Clinical application of breath analysis

Breath analysis has been applied both in cross-sectional and longitudinal studies (Miekisch et al., 2004). In cross-sectional studies, a control group is compared with a disease group, and breath biomarkers are analyzed to identify qualitative or quantitative differences between the two groups. In longitudinal studies, breath biomarkers are observed during the course of a disease or monitoring of pharmacologic interventions. As a result of these studies, several breath biomarkers have been

Future perspective in breath analysis

Clinical usefulness of breath analysis has been well demonstrated in several diagnostic applications; however, a new future in breath analysis is upcoming at an accelerating pace. We have investigated and quantified exhaled VOCs while performing cognitive tasks, consisting of solving the Sudoku puzzles, in patients suffering from diabetes type 2 and in control subjects, using a MOS sensor. The rationale for that was that the brain target areas for insulin are particularly located in the

Conflicts of interest

The authors declare no conflicts of interest in relation to this article.

References (62)

  • A.C. Olin et al.

    Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample

    Chest

    (2006)
  • M. Phillips

    Method for the collection and assay of volatile organic compounds in breath

    Analytical Biochemistry

    (1997)
  • M. Phillips et al.

    Increased breath biomarkers of oxidative stress in diabetes mellitus

    Clinica Chimica Acta

    (2004)
  • M. Phillips et al.

    Detection of lung cancer with volatile markers in the breath

    Chest

    (2003)
  • M. Phillips et al.

    Variation in volatile organic compounds in the breath of normal humans

    Journal of Chromatography B: Biomedical Sciences and Applications

    (1999)
  • T.H. Risby et al.

    Clinical application of breath biomarkers of oxidative stress status

    Free Radical Biology and Medicine

    (1999)
  • J. Romagnuolo et al.

    Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation

    American Journal of Gastroenterology

    (2002)
  • K.D. Skeldon et al.

    Application of laser spectroscopy for measurement of exhaled ethane in patients with lung cancer

    Respiratory Medicine

    (2006)
  • S.J. Szefler et al.

    Asthma Clinical Research Network of the National Heart Lung, and Blood Institute. Significant variability in response to inhaled corticosteroids for persistent asthma

    Journal of Allergy and Clinical Immunology

    (2002)
  • S.J. Szefler et al.

    Asthma outcomes: biomarkers

    Journal of Allergy and Clinical Immunology

    (2012)
  • H. Williams et al.

    Sniffer dogs in the melanoma clinic?

    Lancet

    (1989)
  • ATS/ERS

    ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide

    American Journal of Respiratory and Critical Care Medicine

    (2005)
  • A. Amann et al.

    Methodological issues of sample collection and analysis of exhaled breath

  • W. Cao et al.

    Breath analysis: potential for clinical diagnosis and exposure assessment

    Clinical Chemistry

    (2006)
  • G.E. Carpagnano

    Exhaled breath analysis and sleep

    Journal of Clinical Sleep Medicine

    (2011)
  • S. Chen et al.

    Mercaptans and dimethyl sulfide in the breath of patients with cirrhosis of the liver. Effect of feeding methionine

    Journal of Laboratory and Clinical Medicine

    (1970)
  • J.D. Christie et al.

    Registry for the International Society for Heart and Lung Transplantation: twenty-fifth official adult lung and heart/lung transplantation report

    Journal of Heart and Lung Transplantation

    (2008)
  • E. Clini et al.

    Endogenous nitric oxide in stable COPD patients: correlates with severity of disease

    Thorax

    (1998)
  • K.A. Cope et al.

    Effects of ventilation on the collection of exhaled breath in humans

    Journal of Applied Physics

    (2004)
  • O.B. Crofford et al.

    Acetone in breath and blood

    Transactions of the American Clinical and Climatological Association

    (1977)
  • M. Dahl et al.

    Markers of early disease and prognosis in COPD

    International Journal of COPD

    (2009)
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