Breathborne Biomarkers and the Human Volatilome

Jonathan Beauchamp, Cristina Davis, Joachim Pleil

• Publisher: Elsevier
• Year: 2020
• Edition: 2
• eBook ISBN:
  9780128223970
• Topic: Physical Sciences
• Subtopic: Analytic Chemistry

Breathborne biomarkers carry information on the state of human health, and their role in aiding clinical diagnosis or in therapeutic monitoring has become increasingly important as advances in the field are made. Breathborne Biomarkers and the Human Volatilome, Second Edition, provides a comprehensive update and reworking of the 2013 book Volatile Biomarkers, by Anton Amann and David Smith. The new editing team has expanded this edition beyond volatile organic compounds to cover the broad field of breath analysis, including the many exciting developments that have occurred since the first edition was published. This thoroughly revised volume includes the latest discoveries and applications in breath research from the world's foremost scientists, and offers insights into related future developments. It is an ideal resource for researchers, scientists, and clinicians with an interest in breath analysis. - Presents recent advances in the field of breath analysis - Includes an extensive overview of established biomarkers, detection tools, disease targets, specific applications, data analytics, and study design - Offers a broad treatise of each topic, from basic concepts to a comprehensive review of discoveries, current consensus of understanding, and prospective future developments - Acts as both a primer for beginners and a reference for seasoned researchers

Part C

Analytics

Outline

Chapter 9. Selected ion flow tube mass spectrometry

Chapter 10. Proton transfer reaction—mass spectrometry

Chapter 11. Ion mobility spectrometry

Chapter 12. Secondary electrospray ionization

Chapter 13. Sensor systems

Chapter 14. Optical spectroscopy

Chapter 15. Comprehensive gas chromatography-mass spectrometry

Chapter 16. High-resolution mass spectrometry

Chapter 9

Selected ion flow tube mass spectrometry

David Smith ¹ , Patrik Španěl ² , George B. Hanna ³ , and Raed Dweik ^{4 1} Trans Spectra Limited, Newcastle-under-Lyme, United Kingdom ² J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic ³ Department of Surgery and Cancer, Imperial College, St. Mary's Campus, London, United Kingdom ⁴ Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States

Abstract

Selected ion flow tube mass spectrometry (SIFT-MS) is a chemical ionization technique that offers sensitive, real-time detection of volatile organic compounds (VOCs) down to trace levels. This chapter briefly introduces the technique and summarizes the recent research into SIFT-MS analyses of exhaled breath and the most pertinent results obtained. The search for single-breath VOCs is illustrated by the online quantification by SIFT-MS of ammonia, acetone, hydrogen cyanide, methanol, pentane, and acetic acid. The breathprint approach to the analysis of SIFT-MS spectra is illustrated by several studies of the exhaled breath of patients with several clinical conditions, including heart failure and liver disease. The results of detailed breath SIFT-MS studies in patients with gastroesophageal cancer indicate that VOC profiling may be suitable in identifying those at high risk of this disease. In vitro studies of the VOCs emitted by pulmonary pathogens illustrate the search for exhaled breath biomarkers of airways colonization by such organisms.

Key words

Breath-prints; Cancer; Online breath analysis; Pulmonary pathogens; SIFT-MS; Single VOCs

1. 9.1 Overview
2. 9.2 The search for and quantification of single-breath metabolites related to specific disease and infection
   1. 9.2.1 Ammonia
   2. 9.2.2 Acetone
   3. 9.2.3 Hydrogen cyanide
   4. 9.2.4 Methanol
   5. 9.2.5 Pentane
   6. 9.2.6 Acetic acid
3. 9.3 Full scan spectra identifying breathprints of disease or disorders
4. 9.4 Breath biomarkers of cancer
5. 9.5 In vitro studies of volatile compound emissions from pulmonary pathogens
6. 9.6 Summary
7. References

9.1. Overview

Selected ion flow tube mass spectrometry (SIFT-MS) was first realized as a viable technique for the analysis of trace gases in ambient air in 1996 and its potential for direct online, real-time analysis became immediately obvious. Instrumental development has gone through several phases from a large laboratory-based device to the current mobile commercial analytical instruments. SIFT-MS can be exploited for real-time analysis of volatile trace gases of biological origin, especially in breath, ¹ but also in the headspace of biological fluids, particularly urine, ² and trace compounds emitted by mammalian cell ³ and bacterial cultures ⁴ of clinical significance. The earliest research using SIFT-MS for breath analysis and related topics has been reviewed elsewhere. ⁵ This chapter briefly introduces the technique and then reviews the latest discoveries and developments in SIFT-MS research of clinical relevance.

Selected ion flow tube-mass spectrometry relies on the chemical ionization by selected reagent ions, H₃O⁺, NO⁺, and O₂ ⁺

, of trace analyte compounds in air/breath samples introduced at a controlled flow rate into helium carrier gas passing rapidly through a flow tube. ¹ Reactions occur between the selected reagent ion and the composite analyte molecules that produce characteristic product (analyte) ions and their currents (count rates) are measured by a downstream analytical mass spectrometer/detection system. The identified analyte ions are related to specific neutral trace compounds in the air/breath from an in-depth knowledge of the ion-molecule chemistry. Their count rates, coupled with physical parameters, such as carrier (helium) gas and sample gas flow rates, are converted to concentrations of the neutral trace analyte molecules in the sample. To achieve accurate trace gas analysis, a proper appreciation of the complex ion chemistry occurring in SIFT-MS analytical reactors is needed, especially when humid samples are being analyzed. Thus, an ion kinetics library has been built based on extensive studies of the reactions of the reagent ions with a wide range of volatile organic compounds (VOCs). SIFT-MS allows online, real-time analysis of the trace gases in humid media at atmospheric pressure down to concentrations in parts-per-billion by volume, ppb or lower. ⁶ Thus, directly exhaled breath can be analyzed, which avoids sample collection into bags or onto surface or cryogenic traps that can compromise the sample through losses, artifacts, or incomplete recovery (see Chapter 2).

The raw data from a SIFT-MS analysis of a breath/air sample is usually in the form of a mass spectrum acquired by the downstream analytical mass spectrometer over a chosen range of mass-to-charge ratio, m/z. The peaks on the spectrum are those of the reagent ions and the analyte ions. The kinetics library relates the analyte ions to the VOCs in the sample and treatment of the ion counts and the known kinetics of the reagent ion/VOC reactions allows the quantification of the VOCs. This is called the full scan (FS) mode of analysis. For rapid and precise targeted analyses, the count rates of selected analyte ions are monitored. This is called the multiple ion monitoring (MIM) mode of analysis and is chosen when analyzing single-breath exhalations for several chosen metabolites. An additional valuable feature of online analysis of single exhalations is that on the inhalation cycle through the mouth, the ambient air adjacent to the sampling port can be analyzed, which is very valuable for breath analysis. SIFT-MS is especially suited to direct exhaled breath analysis, principally because of its practical simplicity, as is required for a patient-friendly tool in the clinical environment. Single sequential breath exhalations can be followed over periods of many hours allowing biochemical kinetics to be studied with a large data flow and good temporal definition. ⁷

Notwithstanding these unique online analysis features of SIFT-MS, sample collection followed by offline analysis can be achieved with care, noting the well-reported pitfalls in this procedure and the likely errors and uncertainties that can result (see Chapter 2). Indeed, much data on breath analysis have been obtained by breath collection into polymer bags (predominantly Tedlar or Nalophan) followed by SIFT-MS analysis, because signal integration times can be much longer than are possible for single-breath exhalations. In this manner, both FS and MIM spectra can be accumulated, providing commensurately greater analytical sensitivity. Also, preconcentration of the trace metabolites in collected breath samples using solid-phase microextraction (SPME; widely used together with gas chromatography–mass spectrometry [GC-MS]), can be used in combination with SIFT-MS as the analytical method. Similarly, thermal desorption (TD) has been used together with SIFT-MS. ⁸ A shortcoming of SIFT-MS is that it can be difficult to identify some neutral analyte molecules in mixtures, especially structural isomers, from only their analyte ions. Then, coordinated SPME-GC-MS or TD-GC-MS with SIFT-MS experiments can be exploited, the former providing more positive identification of neutral analytes and the latter providing more accurate quantification as long as the analytical ion chemistry is understood.

9.2. The search for and quantification of single-breath metabolit...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Introducing people to innovations, step by step—the legacy of Anton Amann
• Contributors
• Foreword
• Preface
• Part A. Concepts and modeling
• Part B. Inorganics and non-volatiles
• Part C. Analytics
• Part D. Breath tests
• Part E. Beyond human breath
• Part F. Field applications
• Part G. Design and interpretation
• Index