Evolution of clinical and environmental health applications of exhaled breath research: Review of methods and instrumentation for gas-phase, condensate, and aerosols

Abstract

Human breath, along with urine and blood, has long been one of the three major biological media for assessing human health and environmental exposure. In fact, the detection of odor on human breath, as described by Hippocrates in 400 BC, is considered the first analytical health assessment tool. Although less common in comparison to contemporary bio-fluids analyses, breath has become an attractive diagnostic medium as sampling is non-invasive, unlimited in timing and volume, and does not require clinical personnel. Exhaled breath, exhaled breath condensate (EBC), and exhaled breath aerosol (EBA) are different types of breath matrices used to assess human health and disease state. Over the past 20 years, breath research has made many advances in assessing health state, overcoming many of its initial challenges related to sampling and analysis. The wide variety of sampling techniques and collection devices that have been developed for these media are discussed herein. The different types of sensors and mass spectrometry instruments currently available for breath analysis are evaluated as well as emerging breath research topics, such as cytokines, security and airport surveillance, cellular respiration, and canine olfaction.

Keywords: Analytical techniques; Biomarkers; Breath research; Exhaled breath aerosol (EBA); Exhaled breath condensate (EBC); Volatile organic compounds (VOCs).

Conflict of interest statement

Conflict of Interest Disclosure

The authors declare no competing financial interest.

Published by Elsevier B.V.

Figures

Figure 1:

Comparison of EBC and EBA publication trends Publications featuring EBA and EBC media have increased over the past 20 years, although EBC publication rates have accelerated past those of EBA, with more than double the number of EBC publications than EBA from 2003–2016.

Figure 2:

Mass spectrometry publication comparisons This chart compares the number of publications for LC-MS, Direct-MS, GC-MS and sensors over the past 20 years. All publications in breath research show an upward trend, with most publications reporting breath research results utilizing GC-MS and sensors in recent years.

Figure 3:

High-throughput GC-MS and LC-MS instrumentation for analysis of breath matrices A) ATD-GC/MS; B) ATD-GC-TOF/MS; C) QqQ/MS; D) Q-TOF/MS. Instruments A and B have been utilized to analyze sorbent tubes to assess VOC levels in exhaled breath samples, while C and D have been used to analyze liquid filter extractions to detect EBA collected on different types of breathing masks. Photo credits: Chuck Gaul (U.S. EPA).

Figure 4:

Direct-MS and immunoassay instrumentation utilized in breath research A) PTR-MS; B) IMS; C) SIFT-MS; D) MSD; E) SIMOA HD-1 Analyzer. These instruments can be used for fast analysis of breath samples to analyze VOCs (A, B, and C) and cytokines (D and E). Photo credits: A) Dr. Jonathan Beauchamp; B) Dr. Jorg Ingo Baumbach; C) Dr. Patrik Spanel; D) Brett Winters; E) Chuck Gaul (U.S. EPA).

Figure 5:

Trends in breath alcohol research publications This figure shows the number of papers published from 1960–2016 that discuss breath analysis of alcohol or ethanol. In general, publications have increased over time, with a significant spike in alcohol-related breath publications from 2012–2016.

Figure 6:

Canine olfaction in breath sample classification Canine sniffing of biological samples, including breath, has become a viable method for cancer and disease detection. Dogs are trained to differentiate samples from diseased versus healthy individuals based on scent, providing a potential method for early stage disease diagnosis. Photo credit: Glenn Ferguson from Cancerdogs.