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Breath Analysis

Breath Analysis

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Breath Analysis

444 Seiten
4 Stunden
Nov 29, 2018


Breath Analysis presents state-of-the-art research in this specialized field, also offering guidance on how best to design the technology and conduct analysis. The book primarily focuses on the diagnosis of lung cancer, asthma and Chronic Obstructive Pulmonary Diseases. The reliability, consistency and utility of the results from breath analysis depends on exhaled breath sampling procedures and tools, gas sensor array technology (sensing material and transducer), and finally, medical pertinence and interpretation. The book gives step-by-step procedures and discusses best practice solutions for problems in sample collection, sensor technology, clinical assessment, medical interpretation and data analysis.

The book's primary audience would include biomedical engineers and medical doctors, but it is also useful for hospital technicians, hospital and biomedical SME leading figures, and those in PhD level Engineering and Medicine.

  • Presents an overview of existing breath analysis technology, along with their pros and cons
  • Provides a tool for mapping, bridging and translating different approaches and available devices
  • Covers best practices and procedures for exhaled breath collection
Nov 29, 2018

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Breath Analysis - Academic Press

Breath Analysis

First Edition

Giorgio Pennazza

Marco Santonico

Table of Contents

Cover image

Title page



1: Introduction. Breathprinting: What, Why, How


1 Introduction

2 What: Definition and Background

3 Why: Motivations

4 How: Technology and Methods

5 When: Bottlenecks and Perspectives

6 Where: A Practical Navigator for the Design of an Exhaled Breath-Based Experiment

2: Capturing and Storing Exhaled Breath for Offline Analysis



1 Introduction

2 Considerations for Capture and Storage

3 Sampling Methods (Fig. 2)

4 The Ideal Breath Sampler for Offline Sampling

3: Breathprinting Based Diagnosis, Selected Case Study: U-BIOPRED Project


1 U-BIOPRED: Phenotyping in Severe Asthma by ‘Omics Technology

2 Incorporating Breathomics in U-BIOPRED: From Single Center Studies Toward a Pan-European Multicenter Cohort

3 New Insights and Future Directions of VOC-Based Breathprinting After U-BIOPRED

4: Sensor Systems for Breathprinting: A Review of the Current Technologies for Exhaled Breath Analysis Based on a Sensor Array With the Aim of Integrating Them in a Standard and Shared Procedure


1 Introduction

2 The Fundamentals of Sensory Systems

3 Sensor Array Principles

4 Sensors Array for Breath Analysis

5 Interfaces for Breath Analysis

6 Breath Analysis Applications in the Medical Field

5: Data Analysis


1 Introduction

2 Features Extraction and Patterns Normalization

3 Representation of Multidimensional Patterns

4 Clustering Algorithms

5 Classification

6 Conclusions

6: Breathprinting-Based Diagnosis, Selected Case Study: Nonneoplastic Chronic Diseases


1 Respiratory Diseases

2 Heart Failure

3 Chronic Liver Diseases

4 Conclusions

7: e-Nose Technology: The State of the Art on Lung Cancer Diagnosis


1 Lung Cancer Screening—State of the Art

2 Critical Discussion

3 Future Directions

8: Breathprinting-Based Diagnosis: Case Study: Respiratory Diseases


1 Introduction

2 Asthma


4 Obstructive Sleep Apnea

5 Cystic Fibrosis

6 Interstitial Lung Diseases

7 Respiratory Infections

8 Bronchopulmonary Dysplasia

9 Lung Transplantation

10 Summary

9: Breathprinting in Childhood Asthma


1 Asthma Definition

2 Asthma Prevalence

3 Asthma Subgroups

4 Asthma Management

5 Methods to Monitor Asthma in Children

6 The Challenge

7 Breathomics Definition

8 Breathomics Rationale

9 Breath Sampling and Analysis

10 Breathomics Applications in Childhood Asthma

11 Conclusion

10: Breathprinting Based Diagnosis, Selected Case Study: GCMS and E-Nose Collaborative Approach


1 Lung Cancer Diagnosis

2 Gastrointestinal Disease Diagnosis

3 Future Research Directions

4 Conclusion

11: Breathprinting Roadmap Based on Experts’ Opinions


1 Introduction

Corrado di Natale

Gaetano Rocco

Hossam Haick

Stephen Fowler

Jonathan Beuchamp

2 Conclusion



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No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website:

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).


Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN 978-0-12-814562-3

For information on all Academic Press publications visit our website at

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Paul Brinkman     Department of Respiratory Medicine, University of Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

Arnaldo D'Amico

DIIIE, University of L'aquila, L'aquila, Italy

University Campus Bio-Medico Di Roma, Rome, Italy

Antonio De Vincentis     Department of Geriatrics, Campus Bio-Medico University, Rome, Italy

Corrado Di Natale     Department of Electronic Engineering, University of Rome Tor Vergata, Rome, Italy

Giuliana Ferrante     Department of Science for Health Promotion and Mother and Child Care, University of Palermo, Palermo, Italy

Giuseppe Ferri     DIIIE, University of L'aquila, L'aquila, Italy

Stephen J. Fowler     Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

Fan Gao     Zhejiang University, Hangzhou, China

Ildikó Horváth

National Koranyi Institute for Pulmonology

Semmelweis University, Department of Public Health, Budapest, Hungary

Raffaele Antonelli Incalzi     Department of Geriatrics, Campus Bio-Medico University, Rome, Italy

Helga Kiss     University of Pecs, Pecs, Hungary

Stefania La Grutta     Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy

Filippo Longo     Department of Thoracic Surgery, Campus Bio-Medico University, Rome, Italy

Eugenio Martinelli     Department of Electronic Engineering, University of Rome Tor Vergata, Rome, Italy

Crucitti P.F.     Department of Thoracic Surgery, Campus Bio-Medico University, Rome, Italy

Judit Pákó     National Koranyi Institute for Pulmonology, Budapest, Hungary

Claudio Pedone     Department of Geriatrics, Campus Bio-Medico University, Rome, Italy

Giorgio Pennazza     Unit of Electronics for Sensor Systems, Department of Engineering, Campus Bio-Medico University of Rome, Rome, Italy

Gaetano Rocco     Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

Raffaele Rocco     Division of Thoracic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, United States

Marco Santonico     Unit of Electronics for Sensor Systems, Department of Engineering, Campus Bio-Medico University of Rome, Rome, Italy

Steve Turner     Child Health, University of Aberdeen, Aberdeen, United Kingdom

Min Wang     Zhejiang University, Hangzhou, China

Ping Wang     Zhejiang University, Hangzhou, China

Iain R. White     School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom

Xusheng Zhang     Zhejiang University, Hangzhou, China

Alessandro Zompanti     University Campus Bio-Medico Di Roma, Rome, Italy


Introduction. Breathprinting: What, Why, How

Giorgio Pennazza; Marco Santonico    Unit of Electronics for Sensor Systems, Department of Engineering, Campus Bio-Medico University of Rome, Rome, Italy


What is breathprinting? How can breathprinting be useful in a medical context? How can state-of-the-art breathprinting be performed? "The answer is blowing in the wind¹": the breath is volatile; indeed, elusive, and intrinsically complex. This book tries to make this point, and this first chapter represents its introduction. The main message of the chapter is that breathprinting is effective when the target application is well defined, and the best experimental chain is tailored to the application needs. The crucial points include merging and harmonizing the features of the available technologies, both for exhaled breath sampling and analysis; finalizing the experiment with a thoughtful data fusion between clinical and sensor data; and building up a wide network of the main scientific groups and of the stakeholders supporting an international multicenter study.


Exhaled breath; Breathprinting; Sensor array; Analytical chemistry; Multivariate data analysis; Noninvasive diagnosis

1 Introduction

Physicians sometimes work as detectives: when looking for clues beneath symptoms and test results, they’re trying to find the killer, and catch it with the correct diagnosis. A best practice for a detective should be to prevent a crime; this means, for a physician, to prevent diseases by identifying early symptoms and knowing the possible causes. Thus, disease knowledge and prevention are the key points for timely and correct diagnoses. This hard work is mainly supported by physicians’ expertise, and by instrumental evidence, in which technology plays a fundamental role.

Diagnostic instruments, in general, have the aim of revealing altered conditions of certain parameters (e.g., blood analysis, spirometry) or of presenting a global picture or pattern (e.g., computed tomography, X-rays), with respect to a standard healthy condition (or nondiseased). Very often the access to this information is invasive or minimally invasive, thus lowering the frequency of the monitoring, and affecting the efficacy of the preventive action. Among biological fluids exhaled, breath is accessible with a minimally invasive collection procedure. Exhaled breath represents, also, a rich source of information about the individual's health [1, 2]. Conversely, exhaled breath is a very complex biological fluid, also containing other information about different sources that could affect the patient's health: habits, food and beverage uptake, and environmental factors [3]. Also, when focusing on the patient's health, many comorbidities could influence exhaled breath composition [4, 5]. Additionally, the collection procedure can affect the representativeness of the sample [5, 6].

Before illustrating the technologies for exhaled breath sampling and measurement, and before discussing their effectiveness, it is mandatory to define what exhaled breath analysis is.

This chapter is intended to be a sort of extended summary of the book, introducing the reader to different parts of the work. The idea of this introduction is to guide a researcher, interested in one or more of these aspects, to design his/her experiments by composing the elements for a specific application using state-of-the-art know-how, critical data points, and available technology.

2 What: Definition and Background

The analysis of exhaled breath is an examination procedure that is intrinsically noninvasive (minimally invasive in case of forced exhalation) that can be used for the diagnosis, prognosis, and monitoring of many pathologies and disease conditions. It is performed with different technological approaches for exhaled breath collection and measurement [7, 8]. This definition is composed of three parts: what (the sample, exhaled breath); why (the target application); and how (the technology). These three aspects are covered in this section and the next two.

What is exhaled breath? Exhaled breath is a complex mixture containing more than 3000 volatile organic compounds (VOCs) [8]. The possible sources of such VOCs are [4–6, 8]: inhaled compounds (related to the environment); food intake; metabolic processes (diseased and normal); inflammatory processes; genomic or structural changes (disease-induced or physiological) in the lung epithelium; cancerous cells; abnormal metabolism or altered redox status; bacterial populations in the oral cavity, lungs, and gut.

What is the output of the analysis of exhaled breath, and how can it be used? The output of such a complex mixture of VOCs can be provided in two different modalities: a list of alleged compounds, or a pattern (a fingerprint, a profile) [8, 9]. The utilization (via suitable elaboration) of these outputs depends on the target application: is the research looking for specific VOCs? Or is it addressing a characterization via a pattern of VOCs (a sort of exhaled breath classification, or clustering based on fingerprints)?

Considering the huge number of VOCs composing exhaled breath, it is difficult to obtain a complete list of them without performing successive analyses of the same sample with different settings of the instrument. The different settings allow testers to focus on different compound families. Thus, the question is: when VOCs identification is the main goal, should it be the result of a complete characterization of exhaled breath, or is the investigation looking for specific markers?

The definition of breath analysis contains a multiplicity of compounds originated by a multiplicity of different sources. It also contains a multiplicity of different techniques, methods, and technologies pertaining to engineering and analytical chemistry, and often inspired and designed by the harmonic fusion of these two disciplines. Exhaled breath analysis produces multidimensional data arrays, which require a multiplicity of different techniques for data analysis. And a decomposition process can indeed provide the definition of exhaled breath, in the same way that a prism affects light (see Fig. 1): the light is unique because it is focused on a specific goal. But this alignment, addressed to a specific target, is the result of a multidisciplinary integration.

Fig. 1 Overview of the measure chain developed for a breath analysis application. The multidisciplinary background is integrated in the experiment's design, and harmonized by the target application, which asks for specific arrangements among the available ones. The proposed analogy with light says that when the experiment is well focused on the goal, it means that the parameters used for the instrument settings to convey and direct the light are well defined. Moreover, light's composition is known in all its components.

Multiplicity is the keyword of breath analysis, because it deals with multidimensional data, obtained with a variety of different technologies, treated with many different approaches, addressed to different targets, and interpreted via a multidisciplinary study. This keyword tells you that the research context of breath analysis is rich, but complex. Selecting a specific target, which obviously needs a path to achieve it, can be challenging. Each step of this path involves a selection of the best method or technique for sample collection, measurement, and data analysis. So, the first question to start the journey is why? This is the title of the next section.

3 Why: Motivations

Why would exhaled breath analysis be useful in the medical field? The response comes from a fast (and approximate), but reliable and representative, survey in literature that gives us important numbers telling us that the method is more than just promising [10–15]. In the framework of exhaled breath analysis, since 1996, about 300 papers have been devoted to cancer studies, 83% of which are focused on lung cancer. There are approximately 250 papers studying populations affected by chronic obstructive pulmonary diseases (COPD). More than 1000 studies (using a huge number of different methods) have been conducted to solve the asthma puzzle, and about 100 of them are based on the chemical approach to breath analysis for pediatric asthma. Hepatic diseases are treated in almost 80 works. Congestive heart failure (CHF) is the subject of about 40 studies, while more than 100 are devoted to gastrointestinal pathologies. It is worth noting that 30% of these deal with comorbidities.

It is evident that exhaled breath contains information about the individual health state. It is also evident that exhaled breath contains, in general, information about the individual. When information is diluted in a large-scale data mine, representative of all different contexts, it is difficult to extract the data of interest for a target application. Of about 3000 VOCs composing exhaled breath, indeed, 99% are characteristic of the individual (environment, habits) while only 1% could be specific biomarkers of certain diseases [16]. This is because, looking at exhaled breath as a diagnostic clue, the disease is revealed by the pattern alteration, rather than by the presence of specific compounds (for which accepted breath tests already exist). This approach is well synthesized by Fig. 2, which represents an effective practice for breath analysis.

Fig. 2 schematic overview of the genesis of the breathprint research field. The studies published on exhaled breath converge in an intersection focusing on confounding factors and the simultaneous presence of more than one disease. This research focus is reflected in exhaled breath composition, where information is immersed in the effects of the integration among different concomitant causes, representing it in a characteristic profile, which is often called a breathprint.

This global picture of the possible application of breathprint in the medical field is detailed in Chapters 6–9, dealing with nonneoplastic chronic diseases, lung cancer, respiratory diseases, and pediatric asthma, respectively. Each disease is presented, starting with the consolidated diagnostic technologies, and how they are used with breathprinting. The state of the art of exhaled breath analysis in the study of each pathology is illustrated via a review of a selected case study.

4 How: Technology and Methods

When researchers are performing analysis of exhaled breath, their study is in the context of a multidisciplinary research field called breathomics, which means that they are investigating the chemical and biological composition of the exhaled breath. The question is: what is the goal of such research? When VOC identification is not the primary objective, classification/discrimination requires the definition and characterization of the exhaled breath sample using a qualitative approach, meaning a fingerprint (also named breathprint), or breath pattern or breath profile. Breathomic, breathprint, breath profile, breath pattern: are they synonymous? A literature survey could help answer this question. More than 200 papers say yes, they are synonymous; but after a careful reading of the sole abstracts, differences emerge. All of these terms are used in studies using two approaches (VOCs identification and patterning) in studies based on fingerprinting, in experiments looking for biomarkers and, also, more in general, to illustrate a study with a metabolomics point of view. But, breathomics can be found in no more than 20 studies, with a major part consisting of review papers. Thus, it seems that the term breathomics is often used in papers presenting the research field in general, with its possible declinations. Breathprint, breath profile, and breath pattern are effectively synonymous: papers using these terms are, respectively, around 50, around 60, and almost 100. A careful reading reveals a distinction between two of them (pattern and profile) and breathprint. The first two are often also used for describing mechanical and microbiological patterns, and sometimes to define the output of a breath test (thus referred to specific VOCs). Breathprint, instead, is exclusively used to describe a qualitative picture of the chemical composition of exhaled breath.

Breathprinting starts with:

(1)a device for breathprint capturing (collection and measurement) (treated in Chapters 2–4)

(2)that can be analyzed using a variety of data analysis techniques (treated in Chapter 5)

(3)and interpreted on the basis of a breathprint library (treated in Chapters 6–10)

Thus, describing HOW breathprinting is performed is a step-by-step procedure, described as follows:

Step 1

Factors influencing the selection of the sampling method:

–The influence of the environment background

–The exhaled breath volume to be sampled

–The duration (time) and modality of sampling (blowing, normal breathing)

–Smoking habits

–Food intake

Methods currently available for exhaled breath collection [17–20]:

–Direct delivery of the exhalate from the subject into the device measure cell

–Indirect modality, by using sampling media. Two alternatives:

osampling bags or

oadsorbing cartridges

When comparing sampling bags versus adsorbing cartridges:

–Automatic exhalation delivery in a cartridge (independently on patient's action) is less invasive than blowing in a bag.

–Cartridges offer the following practical advantages:

oThey can be easily stored and transported

oThey can be used as a preconcentration medium

oSampling bags are low cost (with respect to cartridges), but cartridges can be reused

Technologies for exhaled breath analysis, depending on the scientific approach [21–28] include:

(a)VOC identification

–Gas chromatography coupled with mass spectrometry (GC-MS)

–Proton transfer mass spectrometry (PTR-MS)

–Selected ion flow tube mass spectrometry (SIFT-MS)

(b)VOC patterning

Arrays of nonselective gas sensors (4-500), often coupled with pattern recognition techniques specific for multivariate data analysis, often dubbed electronic noses (e-noses), based on many different working principles include:

–Conductive sensors (thin oxide, gold nanoparticles, polymers)

–Quartz microbalances (QMB)

–Optical sensors

–Surface acoustic wave sensors (SAW)

Step 2

We encourage readers to research the numerous multivariate, linear, and nonlinear data analysis techniques, with their acronyms, and pros and cons. A useful and effective selection of them is presented in Chapter 5.

Step 3

To address a specific diagnostic problem, one should research specific instruments and techniques, and also investigate different approaches for data interpretation. Thus, interpretation is presented via a series of case studies devoted to different diseases in Chapters 6–10.

5 When: Bottlenecks and Perspectives

When will breathprinting reach its breakthrough? What are the bottlenecks? [27]. Let us respond by starting from a unique point of view.

System biology is the current, innovative, but well-established, paradigm of a novel and interdisciplinary approach to the study of the complex interactions within biological systems.

Its practical application is often overlooked in an effort to look more closely (inside) at many different biological mechanisms without altering the nature of the systems and their interactions [28]. Thus, looking at many different technologies in the field of sensors, electronics, and informatics, it could be claimed that the applied system biology is achieved via a sort of system technology, able to integrate all the novel opportunities given by nanotechnology, low-power flexible electronics, the IoT (Internet of Things), and a complex organization of sensor networks and systems, by focusing them on a specific target addressed by system biology studies.

This could be the case of a multiparametric noninvasive approach to the monitoring of patients, for which a system technology approach could reveal a future emerging methodology. This is the approach of breathprinting. This approach has the ambition of crossing over the frontier represented by so-called telemedicine, by means of three key elementary blocks:

–wearable, noninvasive, and cheap low-power electronics, interfacing:

–intelligent sensors, able to work together by a:

–Network system for which each patient becomes a point of care for himself or herself, overcoming the at-home or point-of-care approach, making them ubiquitous.

It has been shown that the analysis of exhaled breath (and of other biological fluids noninvasively accessible) may provide information on the health status of an individual. Nonetheless, an approach that simultaneously takes into account the analysis of organic compounds from multiple sources (breath, saliva, urine, exudate) has never been evaluated. Organizing in a network the innovative sensor systems able to perform such analyses could generate a powerful IoT system able to monitor, at home, a huge number of patients. Data elaboration protocols developed in the cloud should be based on suitable diagnostic algorithms, allowing them to speed-up therapy and preventive actions, and improve follow-up procedures.

This ambitious system technology breathprinting, is illustrated in Fig. 3 [29]. The keywords to keep in mind when researching this technology are integration, network, and collaboration. Proper use of this technology could only be feasible when the main scientific groups and stakeholders join forces for a common journey, which is the subject of the next section.

Fig. 3 Future overview of a noninvasive system technology approach to the monitoring of patients and healthy individuals.

6 Where: A Practical Navigator for the Design of an Exhaled Breath-Based Experiment

At this point, we know which scientific machinery we are driving, why to use it, and when it should be used; thus, we have only to find the way. Currently, the best method to reach a destination is to use a navigator. Besides, navigators have been shown to overcome difficulties whenever the topography is unknown, and when the localization signal is missed. A good map is synthesized in Fig. 4. The question is: what is the

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