CME review article
Human exhaled breath analysis

https://doi.org/10.1016/j.anai.2011.02.016Get rights and content

Objective

To review the fast-developing topic of assessment of exhaled breath components to improve the diagnosis and monitoring of respiratory and systemic diseases.

Data Sources

Review of the literature available in monographs and journals.

Study Selection

Articles and overviews on the broad spectrum of existing experimental and routinely applied methods to assess different aspects of human exhaled breath analysis were selected for presentation in this review.

Results

Exhaled breath constitutes more than 3,500 components, the bulk of which are volatile organic compounds in miniature quantities. Many of these characterize the functioning of the organism as a whole (systemic biomarkers), but some are related to processes taking place in the respiratory system and the airways in particular (lung biomarkers). Assessment of lung biomarkers has proven useful in airway inflammatory diseases. It involves direct measurement of gases such as nitric oxide and inflammatory indicators in exhaled breath condensate such as oxidative stress markers (eg, hydrogen peroxide and isoprostanes), nitric oxide derivatives (eg, nitrate and nitrates), arachidonic acid metabolites (eg, prostanoids, leukotrienes, and epoxides), adenosine, and cytokines. Integral approaches have also been suggested, such as exhaled breath temperature measurement and devices of the “electronic nose” type, which enable the capture of approaches have also been suggested, such as exhaled breath temperature measurementexhaled molecular fingerprints (breath prints). Technical factors related to standardization of the different techniques need to be resolved to reach the stage of routine applicability.

Conclusions

Examination of exhaled breath has the potential to change the existing routine approaches in human medicine. The rapidly developing new analytical and computer technologies along with novel, unorthodox ideas are prerequisites for future advances in this field.

Introduction

Biomarkers are quantifiable indicators of physiologic function and disease activity that provide a practical basis for diagnosis and monitoring of pathologic states. They can be measured in different media belonging or emanating from an organism. Circulating blood is pooling together biochemical compounds and metabolites released from different tissues. A plethora of these are released in the ambient environment in the process of gas exchange taking place in the lung alveoli; other moieties are released from the airways to join the mix. More than 3,500 different components have been identified in exhaled breath, with the list continually growing. Several of them are gases, which constitute the bulk of the exhaled breath volume: nitrogen, oxygen, water, and carbon dioxide. Others are mostly volatile organic compounds (VOCs), and their concentration is miniature. Approximately 50% of the identified VOCs are of endogenous origin, and approximately 200 of these trace compounds are detected in average breath samples from the general human population.1 Different sets of compounds account for the individual smell that characterizes a given subject, transient components can impart fluctuations due to the dietary regimen and other ambient influences, and still others can be associated with pathologic metabolisms specific to different disease states. The complex matrix of exhaled breath components is referred to as molecular breath signature.

For many years physicians have been “sniffing” for specific odors in the air their patients exhale, hence the adjectives uremic, hepatic, and acetone found in medical texts to describe exhaled breath in the respective diseases. The limitations of this organoleptic approach were that diseases would be diagnosed at a very advanced stage when the systemic metabolism was totally compromised. Some 4 decades ago Linus Pauling demonstrated that minute amounts of multiple compounds could be detected and quantitatively measured by gas chromatographic analysis of exhaled air and urine vapors.2 Increased levels of some of these compounds are indicative of systemic disorders and extrapulmonary organ failures, which could be referred to as systemic biomarkers. Since that time technological progress has made it possible to develop miniature instruments capable of measuring extremely large numbers of chemical analytes with limits of detection within the nanomolar and picomolar range.3

This marked improvement in the detective power of breath analysis has prompted the exploration of airway diseases by evaluation of biomarkers deriving from the airways and lung structures. These can be referred to as lung biomarkers. The rationale for this approach is based on research performed in the 1980s and early 1990s, when it was recognized that the substrate of asthma symptoms is inflammation of the mucosa and the underlying tissues lining the airways.4 Once the immunologic mechanisms of this pathologic process set in motion, the process carries on with fluctuations despite treatment. Still further, while the vicious cycle of allergic inflammation spins, it brings about remodeling of the airways with early impairment and premature death.5 These phenomena occur as a result of interplay of multiple cellular and fluid-phase ingredients. It was obvious that the invasive approaches, such as bronchoscopy with bronchoalveolar lavage, initially used to decipher the nature of asthma would not be applicable in routine clinical practice. The first noninvasive method that was validated to assess airway inflammation was the examination of induced sputum.6, 7 Although sputum analysis is still a method of reference, it could not establish itself as a routine standard because it is time-consuming, sophisticated, and expensive. It was tempting to look for biomarkers of inflammation directly in the exhaled air.

Section snippets

Directly Determined Components of Exhaled Breath

Gases appearing in the exhaled breath as by-products of different metabolic pathways or after oral ingestion can be detected and quantitated. Thus, ethanol measurement has found wide application in the control of alcohol consumption by drivers. A recent application of interest is the installing of devices called Alcolocks or alcohol interlock systems in certain types of transportation vehicles in Sweden.8 These are automatic control systems that are designed to prevent driving after excessive

Exhaled Breath Temperature

The deep structures of the lung typically have temperatures representative of the body core. The temperatures are determined by the blood flowing along the rich vascular network of the alveoli. The temperature of the inhaled air is tempered during its flow in and out of the branching airways, which have a separate system of blood supply. Because blood is the main carrier of thermal energy maintaining the core body temperature, processes that would modify its flow within the airway walls might

Discussion

The present overview encompasses a broad range of techniques used to assess different aspects of human exhaled breath, some of which are at the proof-of-concept stage of development, whereas others have applied for research or clinical judgment. The more than 15-year-old saga of FeNO measurement is a typical example of the extensive route that needs to be covered. With more than 2,000 publications in PubMed on the topic, there are still controversies about its utility, reflected by the fact

Conclusion

Identifying biomarkers in exhaled breath, directly in the outflowing air or in EBC, is a lucrative approach that would help the diagnosis, monitoring, management, and treatment of systemic and lung diseases. There are 2 different but complementary trends: the creation of technology or the use of integral approaches to examine exhaled breath. Thus, the emphasis on asthma management will gradually shift from judgments made on the basis of subjective symptoms and objective lung function

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