Review
Diagnostic potential of breath analysis—focus on volatile organic compounds

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Abstract

Breath analysis has attracted a considerable amount of scientific and clinical interest during the last decade. In contrast to NO, which is predominantly generated in the bronchial system, volatile organic compounds (VOCs) are mainly blood borne and therefore enable monitoring of different processes in the body. Exhaled ethane and pentane concentrations were elevated in inflammatory diseases. Acetone was linked to dextrose metabolism and lipolysis. Exhaled isoprene concentrations showed correlations with cholesterol biosynthesis. Exhaled levels of sulphur-containing compounds were elevated in liver failure and allograft rejection. Looking at a set of volatile markers may enable recognition and diagnosis of complex diseases such as lung or breast cancer. Due to technical problems of sampling and analysis and a lack of normalization and standardization, huge variations exist between results of different studies. This is among the main reasons why breath analysis could not yet been introduced into clinical practice. This review addresses the basic principles of breath analysis and the diagnostic potential of different volatile breath markers. Analytical procedures, issues concerning biochemistry and exhalation mechanisms of volatile substances, and future developments will be discussed.

Introduction

Analysis of exhaled air enables the observation of biochemical processes in the body in a noninvasive window. The ancient Greek physicians already knew that some diseases could be diagnosed from the characteristic odour of patients' breath. Modern breath analysis started in the 1970s when Pauling et al. [1] determined more than 200 components in human breath using gas chromatography. For more than one decade, the main problems consisted of substance separation and identification. Due to the technical progress of analytical methods achieved in the 1980s and 1990s, these problems could finally be solved, and issues concerning the physiological meaning of the volatile substances and correlations of breath markers with patients' clinical conditions became more and more important [2]. Introducing breath analysis into clinical practice will be the challenge of today and tomorrow.

The bulk matrix of breath is a mixture of nitrogen, oxygen, carbon dioxide, water, and inert gases. The remaining small fraction of human breath consists of trace components occurring in concentrations in the nmol/l–pmol/l (ppbv–pptv) range. Far more than 500 of these compounds have been described. These volatile substances may be generated in the body or may be absorbed as contaminants from the environment. Exogenous molecules, especially halogenated organic compounds, may be analyzed for environmental or expositional issues to assess compound-specific uptake into the body and elimination from the body [3]. In order to monitor metabolic or any pathologic processes in the body, endogenous substances have to be determined.

These endogenous compounds include inorganic gases, such as NO, CO, volatile organic compounds (VOCs) such as ethane, pentane, acetone, isoprene, and other normally nonvolatile substances such as isoprostanes, peroxynitrite or cytokines that can be determined in breath condensate.

During the last two decades, NO has been recognized as a mediator of numerous physiological processes and as a marker of airway inflammation. Exhaled NO can now be determined by commercially available devices and has therefore been investigated in a large number of studies. Exhalation kinetics and relationships with airway diseases have been described in detail [4], [5], [6], [7], [8].

A number of normally nonvolatile substances, such as isoprostanes, cytokines, leukotrienes, or hydrogen peroxide can be found in breath condensate [7], [9].

Quantitative analysis of breath condensate is hampered by a number of serious problems. There is no clear relationship between assumed alveolar or airway concentrations and substance concentrations in the condensate [10]. Furthermore, some of these compounds only have limited stability.

Volatile organic substances such as ethane, pentane, isoprene, or acetone can provide insights into different biochemical processes in the healthy and the diseased human body. In contrast to the nonvolatile substances in breath condensate exhalation, kinetics of volatile organic substances can be approximated according to substance solubilities. In addition, for most of the exhaled organic compounds, there is no problem of stability.

This review is intended to describe the diagnostic potential of endogenous organic volatile substances in human breath. Analytical procedures, problems concerning the physiological meaning of breath markers, and future developments will be discussed.

Section snippets

Origin and properties of endogenous volatile organic biomarkers

Far more than 500 different volatile organic compounds can be detected in the human breath. Most of them however are not of endogenous origin. Endogenous markers, which are commonly used for diagnostic purposes, are hydrocarbons like ethane, pentane and isoprene; oxygen-containing compounds like acetone, acetaldehyde, methanol, ethanol, and 2-propanol; sulphur-containing compounds like dimethylsulfide, methyl, and ethyl mercaptanes; and carbon disulfide and nitrogen-containing substances like

Technical and methodical aspects of breath analysis

Despite a number of very promising results revealing interesting diagnostic properties of different markers, analysis of volatile organic compounds in breath has not yet been introduced into clinical practice. The main obstacles are technical problems, such as sampling, preconcentration, and analysis, as well as basic methodological issues such as normalization and expression of data.

Generally accepted standards of sampling, preconcentration, and analysis do not exist. Hence, reproducibility

Breath markers in certain diseases

During the last decade, a great number of clinical studies have been undertaken exploring the relationships between the chemical composition of exhaled air and patients' clinical status. Main targets of these investigations were different lung diseases, inflammatory and malignant processes in the body, and special diseased states such as allograft rejection and renal failure.

Problems and requirements of breath testing are different depending on whether longitudinal or cross-sectional studies

Conclusion

Breath analysis has attracted a considerable amount of scientific and clinical interest. The large number of studies undertaken during the last decade may convey an idea of the diagnostic potential of exhaled breath markers. In contrast to NO, which is predominantly generated in the bronchial system, volatile organic compounds are mainly blood borne and therefore enable monitoring of different processes in the body. Single substances or sets and patterns of exhaled markers were investigated in

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