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F1000 Med Rep. 2010; 2: 56.
Published online 2010 July 22. doi:  10.3410/M2-56
PMCID: PMC2990505

Clinical applications of breath testing

Abstract

Breath testing has the potential to benefit the medical field as a cost-effective, non-invasive diagnostic tool for diseases of the lung and beyond. With growing evidence of clinical worth, standardization of methods, and new sensor and detection technologies the stage is set for breath testing to gain considerable attention and wider application in upcoming years.

Introduction and context

With each breath exhaled thousands of molecules are expelled, providing a window into the physiological state of the body. The utilization of breath as a medical test has been reported for centuries as demonstrated by Hippocrates in his description of fetor oris and fetor hepaticus in his treatise on breath aroma and disease [1]. Even in modern times clinicians have noted distinct changes in the breath odor of patients with specific diseases such as diabetes, renal failure, and hepatic diseases [2-4]. However, it was Linus Pauling’s milestone discovery of 250 unique substances present in exhaled breath that offered promising insight into breath testing [5]. Since this discovery, breath analysis has rapidly evolved as a new frontier in medical testing for disease states in the lung and beyond [1]. Breath analysis is now used clinically to monitor asthma, diagnose transplant organ rejection, diagnose Helicobacter pylori infection, detect blood alcohol concentration, and monitor breath gases during anesthesia, mechanical ventilation, and respiration, among numerous other applications [1,6,7].

Recent advances

Breath analysis may offer a relatively inexpensive, rapid, and non-invasive method for detecting a variety of diseases. With recent advancements in mass spectrometry (MS) and gas chromatography MS (GC-MS), it is possible to identify thousands of unique substances, such as volatile organic compounds (VOCs) and elemental gases, in the breath [8]. Improved technologies such as selected-ion flow-tube MS (SIFT-MS), multi-capillary column ion mobility MS (MCC-IMS), and proton transfer reaction MS (PTR-MS) have provided real time, precise identification of trace gases in human breath in the parts per trillion range [9-11]. On the other hand, unlike traditional quantitative breath analysis, the electronic nose is essentially trained to recognize odor patterns using an array of gas sensors. The electronic nose has shown accuracy in the detection of lung cancer, pneumonia, and asthma with specificities and sensitivities ranging from 74-98%, as well as in the discrimination between diseases such as chronic obstructive pulmonary disease and asthma [12-15]. Table 1 provides a selected list of the growing number of technologies being applied to breath testing.

Table 1.
Current breath-based test technologies

More recent technological advancements in breath analysis have moved beyond measuring volatiles in the gas phase into measurement of semivolatiles and compounds dissolved in aerosolized droplets in exhaled breath condensate (EBC) and in exhaled breath vapor (EBV). Aerosolized droplets in EBC can be captured by a variety of methods and analyzed for a wide range of biomarkers, such as metabolic end products, proteins, cytokines, and chemokines, with expanding possibilities [16,17]. With 3000 volatile compounds identifiable using EBC and twice the volatile metabolite concentration compared to traditional breath gas analysis, this application has the potential to provide superior information about breathprints of healthy and disease states [8,18]. EBV sampling has also yielded promising results as a new breath sampling method. EBV sampling pre-concentrates breath samples using a solid-phase microextraction fiber inserted into a modified RTube™, a common device also used in EBC sampling. This procedure provides the potential advantages of faster breath sampling and analysis, increased portability, minimal user training, use in contaminated environments, and no requirement for a power source. EBV sampling may yield additional compounds not detected in EBC and may provide greater sensitivity as a sampling method, expanding the spectrum of breath sampling [19].

Implications for clinical practice

The science of breath analysis is rapidly expanding, the technology is improving, and several new applications have been developed or are under commercial development. A major breakthrough over the past decade has been the increase in breath-based tests approved by the US Food and Drug Administration (FDA). Devices measuring common breath gases: oxygen, nitrogen, water vapor, and carbon dioxide in patient respiratory monitoring have served as a platform for technological growth in clinical breath testing applications. In particular, earlier devices, such as those providing the detection of blood alcohol concentration, H. pylori infection, lactose intolerance, and airway monitoring by end-tidal carbon dioxide, have demonstrated clinical benefits as well as diagnostic success in clinical breath testing. Table 2 provides a selected list of the breath-based tests currently approved by the FDA.

Table 2.
Breath-based tests approved by the US Food and Drug Administration [33]

One recent landmark in clinical breath testing occurred in 2003 when the FDA approved the first device that measures the fraction of exhaled nitric oxide (FENO) for asthma monitoring. The desktop NIOX® (currently NIOX® FLEX) was followed by a handheld NIOX® MINO device (both by Aerocrine, Inc., Solna, Sweden) that received FDA clearance in 2008. Advantages provided by FENO monitoring devices include its non-invasive nature, ease of repeat measurements, and use in adult and child populations with severe airflow obstruction where other techniques would be difficult or impossible to perform [20]. FDA approval of these devices has largely been attributed to the standardization of clinical FENO monitoring and detection via breath analysis [21]. In order for this simple yet powerful tool to achieve its potential, we need to further understand the roles that FENO and similar biomarkers of disease play in different clinical settings and across populations, and their specific functions in disease.

A recent clinical application of breath testing has been in the diagnosis of lung cancer. Currently, clinicians rely on relatively expensive and invasive diagnostic tests, such as computed tomography exams, chest radiography, sputum analysis, and lung biopsies, which remain largely ineffective in early stage lung cancer diagnosis. Researchers have demonstrated success using trained dogs in the breath diagnosis of both early and late stage lung cancers with sensitivities and specificities approaching 99%, providing promise for future lung cancer breath tests [22]. Breath testing may provide a promising alternative diagnostic tool for lung cancer as evidenced by numerous studies with specificities and sensitivities ranging from 71-94% [14,23-28]. However, in order to be useful as an upfront screening test for high-risk populations, as a tool to evaluate pulmonary nodules, or as a diagnostic test for lung cancer, a breath test should be at least 90-95% sensitive and specific [29].

As the field of breath research has developed over the past decade, the need for standardization in sampling has grown. Attempts at sampling only critical portions of exhaled breath have proven successful by using end-tidal sampling, as evidenced by finding VOC concentrations most reflective of compounds dissolved in the blood [30]. End-tidal sampling (collecting breath only at the end of exhalation) has shown success over mixed expiratory sampling (collecting the entire exhaled breath) because samples are less likely to be diluted by mixing with dead space volume (inspired air not taking place in gas exchange) and ambient air. A useful application is buffered end-tidal on-line sampling, which measures VOC breath concentrations over a large mass range quickly and uses multiple MS technologies, such as SIFT-MS and PTR-MS, for breath analysis [31]. It is also promising because it uses on-line sampling (the sampling device is connected to the analytical device) versus less accurate off-line sampling (the sample is collected and later brought to the analytical device using reservoirs such as Tedlar® bags). Device calibration and validation have helped by accounting for exogenous VOCs and ambient air contamination in the sampling environment [19]. Since detection of many VOCs occurs at the parts per billion and parts per trillion levels, it is essential to control for exogenous sources of VOCs because ingestion of certain foods, medications, gut bacterial flora, and exposure to chemicals and pollution, amongst many other things, will alter VOCs in exhaled breath [32]. It is important for researchers to consider the change in the concentration of several VOCs in disease states as well as the utility of ranking systems for VOC predictability and new methods for accounting for ambient VOC sources, such as calculating alveolar gradients [8,28]. Despite receiving considerable attention in recent years, issues with standardization have been a major limitation of clinical breath testing. This has been evidenced by difficulties in establishing baseline VOC concentrations and the wide range of results represented in the literature for VOC concentrations in disease. Thus, it is necessary in the future to search for innovative methods for breath research.

There are numerous potential advantages for breath analysis as a clinical test. The method is non-invasive (the sample is relatively easy and painless to acquire), the sample is likely to be rich with information (a single test can scan for signatures of many abnormalities or markers of disease), it has the potential for low cost, and lends itself to easy administration. The field of breath testing has grown tremendously in recent years and with evolving technologies in sampling, sensor design, standardization, and analytical methods breath analysis has the potential to clinically benefit individuals on a global scale in the future.

Acknowledgments

KMP, AM, and RAD are supported by a Third Frontier grant from the Ohio Department of Development. RAD is supported by a National Institutes of Health (NIH) grant (NIH-HL68863).

Abbreviations

EBC
exhaled breath condensate
EBV
exhaled breath vapor
FDA
US Food and Drug Administration
FENO
fraction of exhaled nitric oxide
GC-MS
gas chromatography MS
MCC-IMS
multi-capillary column ion mobility MS
MS
mass spectrometry
PTR-MS
proton transfer reaction MS
SIFT-MS
selected-ion flow-tube MS
VOC
volatile organic compound

Notes

The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/m/content/2/56

Notes

Competing Interests

The authors declare that they have no competing interests.

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