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Shahbazi Khamas S, Van Dijk Y, Abdel-Aziz MI, Neerincx AH, Maarten Blankestijn J, Vijverberg SJH, Hashimoto S, Bush A, Kraneveld AD, Hedman AM, Toncheva AA, Almqvist C, Wolff C, Murray CS, Hedlin G, Roberts G, Adcock IM, Korta-Murua J, Bønnelykke K, Fleming LJ, Pino-Yanes M, Gorenjak M, Kabesch M, Sardón-Prado O, Montuschi P, Singer F, Elosegui PC, Fowler SJ, Brandstetter S, Harner S, Dahlén SE, Potočnik U, Frey U, van Aalderen W, Brinkman P, Maitland-van der Zee AH. Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study. Am J Respir Crit Care Med 2024; 210:1091-1100. [PMID: 38648186 DOI: 10.1164/rccm.202312-2270oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 04/19/2024] [Indexed: 04/25/2024] Open
Abstract
Rationale: The early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. Objectives: To assess the accuracy of gas chromatography-mass spectrometry-based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. Methods: This study encompassed discovery (SysPharmPediA [Systems Pharmacology Approach to Uncontrolled Paediatric Asthma]) and validation (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes] and PANDA [Paediatric-Asthma-Non-Invasive-Diagnostic-Approaches]) phases. First, exhaled VOCs that discriminated degrees of asthma control were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled on the basis of asthma control test scores and the number of severe attacks in the past year. In addition, the potential of VOCs to predict two or more future severe asthma attacks in SysPharmPediA was evaluated. Measurements and Main Results: Complete data were available for 196 children (SysPharmPediA, n = 100; U-BIOPRED, n = 49; PANDA, n = 47). In SysPharmPediA, after randomly splitting the population into training (n = 51) and test (n = 49) sets, three compounds (acetophenone, ethylbenzene, and styrene) distinguished between patients with uncontrolled and controlled asthma. The areas under the receiver operating characteristic curves (AUROCCs) for training and test sets were, respectively, 0.83 (95% confidence interval [CI], 0.65-1.00) and 0.77 (95% CI, 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ± 0.06 (U-BIOPRED) and 0.68 ± 0.05 (PANDA). Attack prediction tests resulted in AUROCCs of 0.71 (95% CI, 0.51-0.91) and 0.71 (95% CI, 0.52-0.90) for the training and test sets. Conclusions: Exhaled metabolite analysis might enable asthma control classification in children. This should stimulate the further development of exhaled metabolite-based point-of-care tests in asthma.
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Affiliation(s)
- Shahriyar Shahbazi Khamas
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Yoni Van Dijk
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Mahmoud I Abdel-Aziz
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Anne H Neerincx
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Jelle Maarten Blankestijn
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Susanne J H Vijverberg
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Simone Hashimoto
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Andrew Bush
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Royal Brompton Hospital, London, United Kingdom
| | - Aletta D Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Anna M Hedman
- Department of Medical Epidemiology and Biostatistics
| | | | - Catarina Almqvist
- Department of Medical Epidemiology and Biostatistics
- Pediatric Allergy and Pulmonology Unit
| | - Christine Wolff
- Science and Development Campus Regensburg, University Children's Hospital Regensburg, Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
| | - Clare S Murray
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
- Manchester Academic Health Science Centre and National Institute for Health and Care Research Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
| | - Gunilla Hedlin
- Department of Women's and Children's Health, and
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Graham Roberts
- National Institute for Health and Care Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and Clinical and Experimental Sciences and Human Development and Health, University of Southampton, Southampton, United Kingdom
| | - Ian M Adcock
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Royal Brompton Hospital, London, United Kingdom
| | - Javier Korta-Murua
- Division of Pediatric Respiratory Medicine, Donostia University Hospital, San Sebastián, Spain
| | - Klaus Bønnelykke
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Louise J Fleming
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Royal Brompton Hospital, London, United Kingdom
| | - Maria Pino-Yanes
- Institute of Biomedical Technologies and
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, University of La Laguna, La Laguna, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Mario Gorenjak
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, and
| | - Michael Kabesch
- Department of Pediatric Pneumology and Allergy and
- Science and Development Campus Regensburg, University Children's Hospital Regensburg, Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
| | - Olaia Sardón-Prado
- Division of Pediatric Respiratory Medicine, Donostia University Hospital, San Sebastián, Spain
- Department of Pediatrics, University of the Basque Country, San Sebastián, Spain
| | - Paolo Montuschi
- Department of Pharmacology, Catholic University of the Sacred Heart, and Agostino Gemelli University Hospital Foundation, IRCCS, Rome, Italy
| | - Florian Singer
- Division of Paediatric Pulmonology and Allergology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Paula Corcuera Elosegui
- Division of Pediatric Respiratory Medicine, Donostia University Hospital, San Sebastián, Spain
| | - Stephen J Fowler
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
- Manchester Academic Health Science Centre and National Institute for Health and Care Research Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
| | - Susanne Brandstetter
- Science and Development Campus Regensburg, University Children's Hospital Regensburg, Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
| | | | - Sven-Erik Dahlén
- Institute of Environmental Medicine and Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden
| | - Uroš Potočnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, and
- Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia
- Department for Science and Research, University Medical Centre Maribor, Maribor, Slovenia; and
| | - Urs Frey
- University Children's Hospital Basel, University of Basel, Basel, Switzerland
| | | | - Paul Brinkman
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
| | - Anke-Hilse Maitland-van der Zee
- Department of Pulmonary Medicine and
- Department of Paediatric Pulmonary Medicine, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands
- Amsterdam Public Health, Amsterdam, the Netherlands
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Chou H, Godbeer L, Allsworth M, Boyle B, Ball ML. Progress and challenges of developing volatile metabolites from exhaled breath as a biomarker platform. Metabolomics 2024; 20:72. [PMID: 38977623 PMCID: PMC11230972 DOI: 10.1007/s11306-024-02142-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 06/13/2024] [Indexed: 07/10/2024]
Abstract
BACKGROUND The multitude of metabolites generated by physiological processes in the body can serve as valuable biomarkers for many clinical purposes. They can provide a window into relevant metabolic pathways for health and disease, as well as be candidate therapeutic targets. A subset of these metabolites generated in the human body are volatile, known as volatile organic compounds (VOCs), which can be detected in exhaled breath. These can diffuse from their point of origin throughout the body into the bloodstream and exchange into the air in the lungs. For this reason, breath VOC analysis has become a focus of biomedical research hoping to translate new useful biomarkers by taking advantage of the non-invasive nature of breath sampling, as well as the rapid rate of collection over short periods of time that can occur. Despite the promise of breath analysis as an additional platform for metabolomic analysis, no VOC breath biomarkers have successfully been implemented into a clinical setting as of the time of this review. AIM OF REVIEW This review aims to summarize the progress made to address the major methodological challenges, including standardization, that have historically limited the translation of breath VOC biomarkers into the clinic. We highlight what steps can be taken to improve these issues within new and ongoing breath research to promote the successful development of the VOCs in breath as a robust source of candidate biomarkers. We also highlight key recent papers across select fields, critically reviewing the progress made in the past few years to advance breath research. KEY SCIENTIFIC CONCEPTS OF REVIEW VOCs are a set of metabolites that can be sampled in exhaled breath to act as advantageous biomarkers in a variety of clinical contexts.
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Hashoul D, Saliba W, Broza YY, Haick H. Non-contact immunological signaling for highly-efficient regulation of the transcriptional map of human monocytes. Bioeng Transl Med 2024; 9:e10519. [PMID: 38818125 PMCID: PMC11135151 DOI: 10.1002/btm2.10519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/18/2023] [Accepted: 03/29/2023] [Indexed: 06/01/2024] Open
Abstract
The different immune system cells communicate and coordinate a response using a complex and evolved language of cytokines and chemokines. These cellular interactions carry out multiple functions in distinct cell types with numerous developmental outcomes. Despite the plethora of different cytokines and their cognate receptors, there is a restricted number of signal transducers and activators to control immune responses. Herein, we report on a new class of immunomodulatory signaling molecules based on volatile molecules (VMs, namely, volatile organic compounds [VOCs]), by which they can affect and/or control immune cell behavior and transcriptomic profile without any physical contact with other cells. The study demonstrates the role of VMs by analyzing non-contact cell communication between normal and cancerous lung cells and U937 monocytes, which are key players in the tumor microenvironment. Integrated transcriptome and proteome analyses showed the suggested regulatory role of VMs released from normal and cancer cells on neighboring monocytes in several molecular pathways, including PI3K/AKT, PPAR, and HIF-1. Presented data provide an initial platform for a new class of immunomodulatory molecules that can potentially mirror the genomic and proteomic profile of cells, thereby paving the way toward non-invasive immunomonitoring.
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Affiliation(s)
- Dina Hashoul
- Department of Chemical Engineering and Russell Berrie Nanotechnology InstituteTechnion ‐ Israel Institute of TechnologyHaifaIsrael
| | - Walaa Saliba
- Department of Chemical Engineering and Russell Berrie Nanotechnology InstituteTechnion ‐ Israel Institute of TechnologyHaifaIsrael
| | - Yoav Y. Broza
- Department of Chemical Engineering and Russell Berrie Nanotechnology InstituteTechnion ‐ Israel Institute of TechnologyHaifaIsrael
| | - Hossam Haick
- Department of Chemical Engineering and Russell Berrie Nanotechnology InstituteTechnion ‐ Israel Institute of TechnologyHaifaIsrael
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Lejeune S, Kaushik A, Parsons ES, Chinthrajah S, Snyder M, Desai M, Manohar M, Prunicki M, Contrepois K, Gosset P, Deschildre A, Nadeau K. Untargeted metabolomic profiling in children identifies novel pathways in asthma and atopy. J Allergy Clin Immunol 2024; 153:418-434. [PMID: 38344970 DOI: 10.1016/j.jaci.2023.09.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 09/19/2023] [Accepted: 09/25/2023] [Indexed: 02/15/2024]
Abstract
BACKGROUND Asthma and other atopic disorders can present with varying clinical phenotypes marked by differential metabolomic manifestations and enriched biological pathways. OBJECTIVE We sought to identify these unique metabolomic profiles in atopy and asthma. METHODS We analyzed baseline nonfasted plasma samples from a large multisite pediatric population of 470 children aged <13 years from 3 different sites in the United States and France. Atopy positivity (At+) was defined as skin prick test result of ≥3 mm and/or specific IgE ≥ 0.35 IU/mL and/or total IgE ≥ 173 IU/mL. Asthma positivity (As+) was based on physician diagnosis. The cohort was divided into 4 groups of varying combinations of asthma and atopy, and 6 pairwise analyses were conducted to best assess the differential metabolomic profiles between groups. RESULTS Two hundred ten children were classified as At-As-, 42 as At+As-, 74 as At-As+, and 144 as At+As+. Untargeted global metabolomic profiles were generated through ultra-high-performance liquid chromatography-tandem mass spectroscopy. We applied 2 independent machine learning classifiers and short-listed 362 metabolites as discriminant features. Our analysis showed the most diverse metabolomic profile in the At+As+/At-As- comparison, followed by the At-As+/At-As- comparison, indicating that asthma is the most discriminant condition associated with metabolomic changes. At+As+ metabolomic profiles were characterized by higher levels of bile acids, sphingolipids, and phospholipids, and lower levels of polyamine, tryptophan, and gamma-glutamyl amino acids. CONCLUSION The At+As+ phenotype displays a distinct metabolomic profile suggesting underlying mechanisms such as modulation of host-pathogen and gut microbiota interactions, epigenetic changes in T-cell differentiation, and lower antioxidant properties of the airway epithelium.
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Affiliation(s)
- Stéphanie Lejeune
- Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; University of Lille, Pediatric Pulmonology and Allergy Department, Hôpital Jeanne de Flandre, CHU Lille, Lille, France; University of Lille, INSERM Unit 1019, CNRS UMR 9017, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France.
| | - Abhinav Kaushik
- Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; Department of Environmental Health, T. H. Chan School of Public Health, Harvard University, Boston, Mass
| | - Ella S Parsons
- Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Sharon Chinthrajah
- Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Michael Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, Calif
| | - Manisha Desai
- Quantitative Science Unit, Department of Medicine, Stanford University School of Medicine, Stanford, Calif
| | - Monali Manohar
- Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Mary Prunicki
- Department of Medicine, Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; Department of Environmental Health, T. H. Chan School of Public Health, Harvard University, Boston, Mass
| | - Kévin Contrepois
- Department of Genetics, Stanford University School of Medicine, Stanford, Calif
| | - Philippe Gosset
- University of Lille, INSERM Unit 1019, CNRS UMR 9017, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France
| | - Antoine Deschildre
- University of Lille, Pediatric Pulmonology and Allergy Department, Hôpital Jeanne de Flandre, CHU Lille, Lille, France; University of Lille, INSERM Unit 1019, CNRS UMR 9017, CHU Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France
| | - Kari Nadeau
- Department of Environmental Health, T. H. Chan School of Public Health, Harvard University, Boston, Mass
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Shahrokny P, Maison N, Riemann L, Ehrmann M, DeLuca D, Schuchardt S, Thiele D, Weckmann M, Dittrich AM, Schaub B, Brinkmann F, Hansen G, Kopp MV, von Mutius E, Rabe KF, Bahmer T, Hohlfeld JM, Grychtol R, Holz O. Increased breath naphthalene in children with asthma and wheeze of the All Age Asthma Cohort (ALLIANCE). J Breath Res 2023; 18:016003. [PMID: 37604132 DOI: 10.1088/1752-7163/acf23e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/21/2023] [Indexed: 08/23/2023]
Abstract
Exhaled breath contains numerous volatile organic compounds (VOCs) known to be related to lung disease like asthma. Its collection is non-invasive, simple to perform and therefore an attractive method for the use even in young children. We analysed breath in children of the multicenter All Age Asthma Cohort (ALLIANCE) to evaluate if 'breathomics' have the potential to phenotype patients with asthma and wheeze, and to identify extrinsic risk factors for underlying disease mechanisms. A breath sample was collected from 142 children (asthma: 51, pre-school wheezers: 55, healthy controls: 36) and analysed using gas chromatography-mass spectrometry (GC/MS). Children were diagnosed according to Global Initiative for Asthma guidelines and comprehensively examined each year over up to seven years. Forty children repeated the breath collection after 24 or 48 months. Most breath VOCs differing between groups reflect the exposome of the children. We observed lower levels of lifestyle-related VOCs and higher levels of the environmental pollutants, especially naphthalene, in children with asthma or wheeze. Naphthalene was also higher in symptomatic patients and in wheezers with recent inhaled corticosteroid use. No relationships with lung function or TH2 inflammation were detected. Increased levels of naphthalene in asthmatics and wheezers and the relationship to disease severity could indicate a role of environmental or indoor air pollution for the development or progress of asthma. Breath VOCs might help to elucidate the role of the exposome for the development of asthma. The study was registered at ClinicalTrials.gov (NCT02496468).
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Affiliation(s)
- P Shahrokny
- Fraunhofer ITEM, Department of Clinical Airway Research, German Center for Lung Research (BREATH, DZL), Hannover, Germany
| | - N Maison
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Germany German Center for Lung Research (CPC-M, DZL), Munich, Germany
- Institute of Asthma and Allergy Prevention, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - L Riemann
- Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, German Center for Lung Research (BREATH, DZL), Hannover, Germany
- Clinician Scientist Program TITUS, Else-Kröner-Fresenius-Stiftung, Hannover Medical School, Hannover, Germany
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - M Ehrmann
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Germany German Center for Lung Research (CPC-M, DZL), Munich, Germany
| | - D DeLuca
- German Center for Lung Research (BREATH, DZL), Hannover, Germany
| | - S Schuchardt
- Fraunhofer ITEM, Bio- and Environmental Analytics, Hannover, Germany
| | - D Thiele
- Division of Pediatric Pulmonology and Allergology, University Children's Hospital, German Center for Lung Research (ARCN, DZL), Luebeck, Germany
- Institute of Medical Biometry and Statistics (IMBS), University Medical Center Schleswig-Holstein, Luebeck, Germany
| | - M Weckmann
- Division of Pediatric Pulmonology and Allergology, University Children's Hospital, German Center for Lung Research (ARCN, DZL), Luebeck, Germany
- Epigenetics of Chronic Lung Disease, Priority Research Area Chronic Lung Diseases, Leibniz Lung Research Center Borstel, Borstel, Germany
| | - A M Dittrich
- Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, German Center for Lung Research (BREATH, DZL), Hannover, Germany
| | - B Schaub
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Germany German Center for Lung Research (CPC-M, DZL), Munich, Germany
| | - F Brinkmann
- Division of Pediatric Pulmonology and Allergology, University Children's Hospital, German Center for Lung Research (ARCN, DZL), Luebeck, Germany
| | - G Hansen
- Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, German Center for Lung Research (BREATH, DZL), Hannover, Germany
| | - M V Kopp
- Division of Pediatric Pulmonology and Allergology, University Children's Hospital, German Center for Lung Research (ARCN, DZL), Luebeck, Germany
- Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - E von Mutius
- Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Germany German Center for Lung Research (CPC-M, DZL), Munich, Germany
- Institute of Asthma and Allergy Prevention, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - K F Rabe
- LungenClinic Grosshansdorf and Department of Medicine, Christian-Albrechts-University Kiel, German Center for Lung Research (ARCN, DZL), Grosshansdorf, Germany
| | - T Bahmer
- LungenClinic Grosshansdorf and Department of Medicine, Christian-Albrechts-University Kiel, German Center for Lung Research (ARCN, DZL), Grosshansdorf, Germany
- Internal Medicine Department I, University Hospital Schleswig-Holstein, UKSH - Campus Kiel, German Center for Lung Research (ARCN, DZL), Kiel, Germany
| | - J M Hohlfeld
- Fraunhofer ITEM, Department of Clinical Airway Research, German Center for Lung Research (BREATH, DZL), Hannover, Germany
- Department of Respiratory Medicine, Hannover Medical School (MHH), Hannover, Germany
| | - R Grychtol
- Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, German Center for Lung Research (BREATH, DZL), Hannover, Germany
| | - O Holz
- Fraunhofer ITEM, Department of Clinical Airway Research, German Center for Lung Research (BREATH, DZL), Hannover, Germany
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Peel A, Wang R, Ahmed W, White I, Wilkinson M, Loke YK, Wilson AM, Fowler SJ. Changes in exhaled volatile organic compounds following indirect bronchial challenge in suspected asthma. Thorax 2023; 78:966-973. [PMID: 37495368 DOI: 10.1136/thorax-2022-219708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/14/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Inhaled mannitol provokes bronchoconstriction via mediators released during osmotic degranulation of inflammatory cells, and, hence represents a useful diagnostic test for asthma and model for acute attacks. We hypothesised that the mannitol challenge would trigger changes in exhaled volatile organic compounds (VOCs), generating both candidate biomarkers and novel insights into their origin. METHODS Participants with a clinical diagnosis of asthma, or undergoing investigation for suspected asthma, were recruited. Inhaled mannitol challenges were performed, followed by a sham challenge after 2 weeks in participants with bronchial hyper-responsiveness (BHR). VOCs were collected before and after challenges and analysed using gas chromatography-mass spectrometry. RESULTS Forty-six patients (mean (SD) age 52 (16) years) completed a mannitol challenge, of which 16 (35%) were positive, and 15 of these completed a sham challenge. Quantities of 16 of 51 identified VOCs changed following mannitol challenge (p<0.05), of which 11 contributed to a multivariate sparse partial least square discriminative analysis model, with a classification error rate of 13.8%. Five of these 16 VOCs also changed (p<0.05) in quantity following the sham challenge, along with four further VOCs. In patients with BHR to mannitol distinct postchallenge VOC signatures were observed compared with post-sham challenge. CONCLUSION Inhalation of mannitol was associated with changes in breath VOCs, and in people with BHR resulted in a distinct exhaled breath profile when compared with a sham challenge. These differentially expressed VOCs are likely associated with acute airway inflammation and/or bronchoconstriction and merit further investigation as potential biomarkers in asthma.
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Affiliation(s)
- Adam Peel
- Respiratory medicine, Norfolk Community Health and Care NHS Trust, Norwich, Norfolk, UK
| | - Ran Wang
- Division of Immunology, Immunity to infection & Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
- Department of Respiratory Medicine, Manchester University NHS Foundation Trust, Manchester, UK
| | - Waqar Ahmed
- Division of Immunology, Immunity to infection & Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Iain White
- Division of Immunology, Immunity to infection & Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
- Laboratory for Environmental and Life Sciences, University of Nova Gorica, Nova Gorica, Slovenia
| | - Maxim Wilkinson
- Division of Immunology, Immunity to infection & Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Yoon K Loke
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK
- Department of Respiratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK
| | - Andrew M Wilson
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK
- Department of Respiratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK
| | - Stephen J Fowler
- Division of Immunology, Immunity to infection & Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK
- Department of Respiratory Medicine, Manchester University NHS Foundation Trust, Manchester, UK
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7
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Romero-Tapia SDJ, Becerril-Negrete JR, Castro-Rodriguez JA, Del-Río-Navarro BE. Early Prediction of Asthma. J Clin Med 2023; 12:5404. [PMID: 37629446 PMCID: PMC10455492 DOI: 10.3390/jcm12165404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/26/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
The clinical manifestations of asthma in children are highly variable, are associated with different molecular and cellular mechanisms, and are characterized by common symptoms that may diversify in frequency and intensity throughout life. It is a disease that generally begins in the first five years of life, and it is essential to promptly identify patients at high risk of developing asthma by using different prediction models. The aim of this review regarding the early prediction of asthma is to summarize predictive factors for the course of asthma, including lung function, allergic comorbidity, and relevant data from the patient's medical history, among other factors. This review also highlights the epigenetic factors that are involved, such as DNA methylation and asthma risk, microRNA expression, and histone modification. The different tools that have been developed in recent years for use in asthma prediction, including machine learning approaches, are presented and compared. In this review, emphasis is placed on molecular mechanisms and biomarkers that can be used as predictors of asthma in children.
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Affiliation(s)
- Sergio de Jesus Romero-Tapia
- Health Sciences Academic Division (DACS), Juarez Autonomous University of Tabasco (UJAT), Villahermosa 86040, Mexico
| | - José Raúl Becerril-Negrete
- Department of Clinical Immunopathology, Universidad Autónoma del Estado de México, Toluca 50000, Mexico;
| | - Jose A. Castro-Rodriguez
- Department of Pediatric Pulmonology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile;
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Savito L, Scarlata S, Bikov A, Carratù P, Carpagnano GE, Dragonieri S. Exhaled volatile organic compounds for diagnosis and monitoring of asthma. World J Clin Cases 2023; 11:4996-5013. [PMID: 37583852 PMCID: PMC10424019 DOI: 10.12998/wjcc.v11.i21.4996] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/08/2023] [Accepted: 07/06/2023] [Indexed: 07/26/2023] Open
Abstract
The asthmatic inflammatory process results in the generation of volatile organic compounds (VOCs), which are subsequently secreted by the airways. The study of these elements through gas chromatography-mass spectrometry (GC-MS), which can identify individual molecules with a discriminatory capacity of over 85%, and electronic-Nose (e-NOSE), which is able to perform a quick onboard pattern-recognition analysis of VOCs, has allowed new prospects for non-invasive analysis of the disease in an "omics" approach. In this review, we aim to collect and compare the progress made in VOCs analysis using the two methods and their instrumental characteristics. Studies have described the potential of GC-MS and e-NOSE in a multitude of relevant aspects of the disease in both children and adults, as well as differential diagnosis between asthma and other conditions such as wheezing, cystic fibrosis, COPD, allergic rhinitis and last but not least, the accuracy of these methods compared to other diagnostic tools such as lung function, FeNO and eosinophil count. Due to significant limitations of both methods, it is still necessary to improve and standardize techniques. Currently, e-NOSE appears to be the most promising aid in clinical practice, whereas GC-MS, as the gold standard for the structural analysis of molecules, remains an essential tool in terms of research for further studies on the pathophysiologic pathways of the asthmatic inflammatory process. In conclusion, the study of VOCs through GC-MS and e-NOSE appears to hold promise for the non-invasive diagnosis, assessment, and monitoring of asthma, as well as for further research studies on the disease.
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Affiliation(s)
- Luisa Savito
- Department of Internal Medicine, Unit of Respiratory Pathophysiology and Thoracic Endoscopy, Fondazione Policlinico Universitario Campus Bio Medico, Rome 00128, Italy
| | - Simone Scarlata
- Department of Internal Medicine, Unit of Respiratory Pathophysiology and Thoracic Endoscopy, Fondazione Policlinico Universitario Campus Bio Medico, Rome 00128, Italy
| | - Andras Bikov
- Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, United Kingdom
| | - Pierluigi Carratù
- Department of Internal Medicine "A.Murri", University of Bari "Aldo Moro", Bari 70124, Italy
| | | | - Silvano Dragonieri
- Department of Respiratory Diseases, University of Bari, Bari 70124, Italy
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9
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Weber R, Streckenbach B, Welti L, Inci D, Kohler M, Perkins N, Zenobi R, Micic S, Moeller A. Online breath analysis with SESI/HRMS for metabolic signatures in children with allergic asthma. Front Mol Biosci 2023; 10:1154536. [PMID: 37065443 PMCID: PMC10102578 DOI: 10.3389/fmolb.2023.1154536] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/16/2023] [Indexed: 04/03/2023] Open
Abstract
Introduction: There is a need to improve the diagnosis and management of pediatric asthma. Breath analysis aims to address this by non-invasively assessing altered metabolism and disease-associated processes. Our goal was to identify exhaled metabolic signatures that distinguish children with allergic asthma from healthy controls using secondary electrospray ionization high-resolution mass spectrometry (SESI/HRMS) in a cross-sectional observational study. Methods: Breath analysis was performed with SESI/HRMS. Significant differentially expressed mass-to-charge features in breath were extracted using the empirical Bayes moderated t-statistics test. Corresponding molecules were putatively annotated by tandem mass spectrometry database matching and pathway analysis. Results: 48 allergic asthmatics and 56 healthy controls were included in the study. Among 375 significant mass-to-charge features, 134 were putatively identified. Many of these could be grouped to metabolites of common pathways or chemical families. We found several pathways that are well-represented by the significant metabolites, for example, lysine degradation elevated and two arginine pathways downregulated in the asthmatic group. Assessing the ability of breath profiles to classify samples as asthmatic or healthy with supervised machine learning in a 10 times repeated 10-fold cross-validation revealed an area under the receiver operating characteristic curve of 0.83. Discussion: For the first time, a large number of breath-derived metabolites that discriminate children with allergic asthma from healthy controls were identified by online breath analysis. Many are linked to well-described metabolic pathways and chemical families involved in pathophysiological processes of asthma. Furthermore, a subset of these volatile organic compounds showed high potential for clinical diagnostic applications.
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Affiliation(s)
- Ronja Weber
- Department of Respiratory Medicine, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Bettina Streckenbach
- Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Lara Welti
- Department of Respiratory Medicine, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Demet Inci
- Department of Respiratory Medicine, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Malcolm Kohler
- Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
| | - Nathan Perkins
- Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Renato Zenobi
- Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Srdjan Micic
- Department of Respiratory Medicine, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Alexander Moeller
- Department of Respiratory Medicine, University Children’s Hospital Zurich, Zurich, Switzerland
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10
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Romijn M, van Kaam AH, Fenn D, Bos LD, van den Akker CHP, Finken MJJ, Rotteveel J, Cerullo J, Brinkman P, Onland W. Exhaled Volatile Organic Compounds for Early Prediction of Bronchopulmonary Dysplasia in Infants Born Preterm. J Pediatr 2023:113368. [PMID: 36868304 DOI: 10.1016/j.jpeds.2023.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/10/2023] [Accepted: 02/12/2023] [Indexed: 03/05/2023]
Abstract
OBJECTIVE(S) To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. METHODS Exhaled breath was collected from infants born <30 weeks' gestation at days 3 and 7 of life. Ion-fragments detected by gas-Chromatography-mass-spectrometry analysis were used to derive and internally validate a VOC prediction model for moderate or severe BPD at 36 weeks postmenstrual age. We tested the predictive performance of the National Institute of Child Health and Human Development (NICHD) clinical BPD prediction model with and without VOCs. RESULTS Breath samples were collected from 117 infants (mean gestation 26.8 [±1.5] weeks). Thirty-three percent of the infants developed moderate or severe BPD. The VOC model showed a c-statistic of 0.89 (95% confidence interval [CI] 0.80-0.97) and 0.92 (95% CI 0.84-0.99)) for the prediction of BPD at days 3 and 7, respectively. Adding the VOCs to the clinical prediction model in non-invasive supported infants resulted in significant improvement in discriminative power on both days (day 3: c-statistic 0.83 versus 0.92, p-value 0.04; day 7: c-statistic 0.82 versus 0.94, p-value 0.03). CONCLUSIONS This study showed that VOC profiles in exhaled breath of preterm infants on non-invasive support in the first week of life differ between those developing and not developing BPD. Adding VOCs to a clinical prediction model significantly improved its discriminative performance.
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Affiliation(s)
- Michelle Romijn
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics-Neonatology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pediatric-Endocrinology, Boelelaan 1117, Amsterdam, the Netherlands
| | - Anton H van Kaam
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics-Neonatology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands
| | - Dominic Fenn
- Amsterdam UMC location University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of laboratory of Experimental Intensive Care and Anaesthesiology, Meibergdreef 9, Amsterdam, the Netherlands
| | - Lieuwe D Bos
- Amsterdam UMC location University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of laboratory of Experimental Intensive Care and Anaesthesiology, Meibergdreef 9, Amsterdam, the Netherlands
| | - Chris H P van den Akker
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics-Neonatology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands
| | - Martijn J J Finken
- Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pediatric-Endocrinology, Boelelaan 1117, Amsterdam, the Netherlands
| | - Joost Rotteveel
- Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pediatric-Endocrinology, Boelelaan 1117, Amsterdam, the Netherlands
| | - Julia Cerullo
- Division of Neonatolgy "Villa dei Fiori" Hospital, Acerra, Naples, Italy
| | - Paul Brinkman
- Amsterdam UMC location University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, the Netherlands
| | - Wes Onland
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics-Neonatology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands.
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Exhaled Breath Analysis for Investigating the Use of Inhaled Corticosteroids and Corticosteroid Responsiveness in Wheezing Preschool Children. J Clin Med 2022; 11:jcm11175160. [PMID: 36079088 PMCID: PMC9456576 DOI: 10.3390/jcm11175160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/28/2022] Open
Abstract
Exhaled breath analysis has great potential in diagnosing various respiratory and non-respiratory diseases. In this study, we investigated the influence of inhaled corticosteroids (ICS) on exhaled volatile organic compounds (VOCs) of wheezing preschool children. Furthermore, we assessed whether exhaled VOCs could predict a clinical steroid response in wheezing preschool children. We performed a crossover 8-week ICS trial, in which 147 children were included. Complete data were available for 89 children, of which 46 children were defined as steroid-responsive. Exhaled VOCs were measured by GC-tof-MS. Statistical analysis by means of Random Forest was used to investigate the effect of ICS on exhaled VOCs. A set of 20 VOCs could best discriminate between measurements before and after ICS treatment, with a sensitivity of 73% and specificity of 67% (area under ROC curve = 0.72). Most discriminative VOCs were branched C11H24, butanal, octanal, acetic acid and methylated pentane. Other VOCs predominantly included alkanes. Regularised multivariate analysis of variance (rMANOVA) was used to determine treatment response, which showed a significant effect between responders and non-responders (p < 0.01). These results show that ICS significantly altered the exhaled breath profiles of wheezing preschool children, irrespective of clinical treatment response. Furthermore, exhaled VOCs were capable of determining corticosteroid responsiveness in wheezing preschool children.
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12
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Influence of Home Indoor Dampness Exposure on Volatile Organic Compounds in Exhaled Breath of Mothers and Their Infants: The NELA Birth Cohort. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12146864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Currently, the effect of exposure to indoor air contaminants and the presence of dampness at home on respiratory/atopic health is of particular concern to physicians. The measurement of volatile organic compounds (VOCs) in exhaled breath is a useful approach for monitoring environmental exposures. A great advantage of this strategy is that it allows the study of the impact of pollutants on the metabolism through a non-invasive method. In this paper, the levels of nine VOCs (acetone, isoprene, toluene, p/m-xylene, o-xylene, styrene, benzaldehyde, naphthalene, and 2-ethyl-1-hexanol) in the exhaled breath of subjects exposed and not exposed to home dampness were assessed. Exhaled breath samples were collected from 337 mother–child pairs of a birth cohort and analysed by gas-chromatography–mass-spectrometry. It was observed that the levels of 2-ethyl-1-hexanol in the exhaled breath of the mothers were significantly influenced by exposure to household humidity. In the case of the infants, differences in some of the VOC levels related to home dampness exposure; however, they did not reach statistical significance. In addition, it was also found that the eosinophil counts of the mothers exposed to home dampness were significantly elevated compared to those of the non-exposed mothers. To our knowledge, these findings show, for the first time, that exposure to home dampness may influence VOC patterns in exhaled breath.
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13
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Li J, Fu Y, Jing W, Li J, Wang X, Chen J, Sun S, Yue H, Dai Y. Biomarkers of Mycoplasma pneumoniae pneumonia in children by urine metabolomics based on Q Exactive liquid chromatography/tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2022; 36:e9234. [PMID: 34897870 DOI: 10.1002/rcm.9234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 06/14/2023]
Abstract
RATIONALE Mycoplasma pneumoniae has become one of the common pathogens causing pediatric respiratory infections. In clinical diagnosis, throat swabs are very difficult to obtain from children, and there is a possibility of false positive results; hence, there are few clinically available diagnostic methods. METHODS In this study, Q Exactive liquid chromatography/tandem mass spectrometry was used to analyze the metabolites in the urine of healthy children (HC) and M. pneumoniae pneumonia in children (MPPC) patients. A multivariate statistical analysis was performed to screen the differential metabolites. Based on the HMDB and KEGG, the possible metabolic pathways subject to biological alteration were identified. RESULTS Compared with HC, 73 different metabolites in MPPC patients disrupted nine metabolic pathways through different change trends; after integrating various parameters, 20 significantly different metabolites were identified as MPPC potential biomarkers. Through the above two analysis modes, acetylphosphate and 2,5-dioxopentanoate were both screened out and used as potential biomarkers for the early diagnosis of MPPC for the first time. CONCLUSIONS The characterization of 20 potential biomarkers provides a scientific basis for predicting and diagnosing MPPC. This article further indicates that urine metabolic profiling has great potential in diagnosing MPPC and can effectively prevent the disease from causing further deterioration.
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Affiliation(s)
- Jing Li
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yunhua Fu
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Changchun University of Chinese Medicine, Changchun, China
| | - Wei Jing
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jie Li
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Xin Wang
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jialing Chen
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Shuxin Sun
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Hao Yue
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Changchun University of Chinese Medicine, Changchun, China
| | - Yulin Dai
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Changchun University of Chinese Medicine, Changchun, China
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14
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Gautam Y, Johansson E, Mersha TB. Multi-Omics Profiling Approach to Asthma: An Evolving Paradigm. J Pers Med 2022; 12:jpm12010066. [PMID: 35055381 PMCID: PMC8778153 DOI: 10.3390/jpm12010066] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/23/2021] [Accepted: 12/28/2021] [Indexed: 02/04/2023] Open
Abstract
Asthma is a complex multifactorial and heterogeneous respiratory disease. Although genetics is a strong risk factor of asthma, external and internal exposures and their interactions with genetic factors also play important roles in the pathophysiology of asthma. Over the past decades, the application of high-throughput omics approaches has emerged and been applied to the field of asthma research for screening biomarkers such as genes, transcript, proteins, and metabolites in an unbiased fashion. Leveraging large-scale studies representative of diverse population-based omics data and integrating with clinical data has led to better profiling of asthma risk. Yet, to date, no omic-driven endotypes have been translated into clinical practice and management of asthma. In this article, we provide an overview of the current status of omics studies of asthma, namely, genomics, transcriptomics, epigenomics, proteomics, exposomics, and metabolomics. The current development of the multi-omics integrations of asthma is also briefly discussed. Biomarker discovery following multi-omics profiling could be challenging but useful for better disease phenotyping and endotyping that can translate into advances in asthma management and clinical care, ultimately leading to successful precision medicine approaches.
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15
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Metabolomics, Microbiota, and In Vivo and In Vitro Biomarkers in Type 2 Severe Asthma: A Perspective Review. Metabolites 2021. [PMID: 34677362 DOI: 10.3390/metabo11100647.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient; thus, it could be a new approach for the management of severe asthma that considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. Metabolomics is the systematic study of low molecular weight (bio)chemicals in a given biological system and offers a powerful approach to biomarker discovery and elucidating disease mechanisms. In this point of view, metabolomics could play a key role in targeting precision medicine.
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16
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Caruso C, Colantuono S, Nicoletti A, Arasi S, Firinu D, Gasbarrini A, Coppola A, Di Michele L. Metabolomics, Microbiota, and In Vivo and In Vitro Biomarkers in Type 2 Severe Asthma: A Perspective Review. Metabolites 2021; 11:metabo11100647. [PMID: 34677362 PMCID: PMC8541451 DOI: 10.3390/metabo11100647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open
Abstract
Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient; thus, it could be a new approach for the management of severe asthma that considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. Metabolomics is the systematic study of low molecular weight (bio)chemicals in a given biological system and offers a powerful approach to biomarker discovery and elucidating disease mechanisms. In this point of view, metabolomics could play a key role in targeting precision medicine.
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Affiliation(s)
- Cristiano Caruso
- Allergy Unit, Fondazione Policlinico A. Gemelli, IRCCS, Catholic University of the Sacred Heart, 00100 Rome, Italy;
- Correspondence:
| | - Stefania Colantuono
- Allergy Unit, Fondazione Policlinico A. Gemelli, IRCCS, Catholic University of the Sacred Heart, 00100 Rome, Italy;
- Digestive Disease Center, Medical and Surgical Sciences Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Sacred Heart, 00100 Rome, Italy;
| | - Alberto Nicoletti
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Department of Internal Medicine, Catholic University of the Sacred Heart, 00100 Rome, Italy;
| | - Stefania Arasi
- Area of Translational Research in Pediatric Specialities, Allergy Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
| | - Davide Firinu
- Department of Medical Sciences and Public Health, University of Cagliari, 09100 Cagliari, Italy;
| | - Antonio Gasbarrini
- Digestive Disease Center, Medical and Surgical Sciences Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Sacred Heart, 00100 Rome, Italy;
| | - Angelo Coppola
- Division of Respiratory Medicine, Ospedale San Filippo Neri-ASL Roma 1, 00100 Rome, Italy;
- UniCamillus, Saint Camillus International, University of Health Sciences, 00131 Rome, Italy
| | - Loreta Di Michele
- Pulmonary Interstitial Diseases Unit, UOSD Interstiziopatie Polmonari Az Osp. S. Camillo-Forlanini, 00100 Rome, Italy;
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17
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Sola-Martínez RA, Lozano-Terol G, Gallego-Jara J, Morales E, Cantero-Cano E, Sanchez-Solis M, García-Marcos L, Jiménez-Guerrero P, Noguera-Velasco JA, Cánovas Díaz M, de Diego Puente T. Exhaled volatilome analysis as a useful tool to discriminate asthma with other coexisting atopic diseases in women of childbearing age. Sci Rep 2021; 11:13823. [PMID: 34226570 PMCID: PMC8257728 DOI: 10.1038/s41598-021-92933-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of asthma is considerably high among women of childbearing age. Most asthmatic women also often have other atopic disorders. Therefore, the differentiation between patients with atopic diseases without asthma and asthmatics with coexisting diseases is essential to avoid underdiagnosis of asthma and to design strategies to reduce symptom severity and improve quality of life of patients. Hence, we aimed for the first time to conduct an analysis of volatile organic compounds in exhaled breath of women of childbearing age as a new approach to discriminate between asthmatics with other coexisting atopic diseases and non-asthmatics (with or without atopic diseases), which could be a helpful tool for more accurate asthma detection and monitoring using a noninvasive technique in the near future. In this study, exhaled air samples of 336 women (training set (n = 211) and validation set (n = 125)) were collected and analyzed by thermal desorption coupled with gas chromatography-mass spectrometry. ASCA (ANOVA (analysis of variance) simultaneous component analysis) and LASSO + LS (least absolute shrinkage and selection operator + logistic regression) were employed for data analysis. Fifteen statistically significant models (p-value < 0.05 in permutation tests) that discriminated asthma with other coexisting atopic diseases in women of childbearing age were generated. Acetone, 2-ethyl-1-hexanol and a tetrahydroisoquinoline derivative were selected as discriminants of asthma with other coexisting atopic diseases. In addition, carbon disulfide, a tetrahydroisoquinoline derivative, 2-ethyl-1-hexanol and decane discriminated asthma disease among patients with other atopic disorders. Results of this study indicate that refined metabolomic analysis of exhaled breath allows asthma with other coexisting atopic diseases discrimination in women of reproductive age.
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Affiliation(s)
- Rosa A Sola-Martínez
- Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
| | - Gema Lozano-Terol
- Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
| | - Julia Gallego-Jara
- Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
| | - Eva Morales
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
- Department of Public Health Sciences, University of Murcia, Murcia, Spain
| | | | - Manuel Sanchez-Solis
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
- Respiratory and Allergy Units, Arrixaca Children's University Hospital, University of Murcia, Murcia, Spain
- Department of Paediatrics, University of Murcia, Murcia, Spain
- Network of Asthma and Adverse and Allergy Reactions (ARADyAL), Health Institute Carlos III, Madrid, Spain
| | - Luis García-Marcos
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
- Respiratory and Allergy Units, Arrixaca Children's University Hospital, University of Murcia, Murcia, Spain
- Department of Paediatrics, University of Murcia, Murcia, Spain
- Network of Asthma and Adverse and Allergy Reactions (ARADyAL), Health Institute Carlos III, Madrid, Spain
| | - Pedro Jiménez-Guerrero
- Regional Atmospheric Modelling Group, Department of Physics, University of Murcia, Murcia, Spain
| | - José A Noguera-Velasco
- Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
- Molecular Therapy and Biomarkers Research Group, Clinical Analysis Service, University Clinical Hospital "Virgen de la Arrixaca", University of Murcia, Murcia, Spain
| | - Manuel Cánovas Díaz
- Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain
| | - Teresa de Diego Puente
- Department of Biochemistry and Molecular Biology B and Immunology, University of Murcia, Murcia, Spain.
- Biomedical Research Institute of Murcia, IMIB-Arrixaca, Murcia, Spain.
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Feizi N, Hashemi-Nasab FS, Golpelichi F, Saburouh N, Parastar H. Recent trends in application of chemometric methods for GC-MS and GC×GC-MS-based metabolomic studies. Trends Analyt Chem 2021. [DOI: 10.1016/j.trac.2021.116239] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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19
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Sola Martínez RA, Pastor Hernández JM, Yanes Torrado Ó, Cánovas Díaz M, de Diego Puente T, Vinaixa Crevillent M. Exhaled volatile organic compounds analysis in clinical pediatrics: a systematic review. Pediatr Res 2021; 89:1352-1363. [PMID: 32919397 DOI: 10.1038/s41390-020-01116-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 07/09/2020] [Accepted: 08/04/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Measured exhaled volatile organic compounds (VOCs) in breath also referred to as exhaled volatilome have been long claimed as a potential source of non-invasive and clinically applicable biomarkers. However, the feasibility of using exhaled volatilome in clinical practice remains to be demonstrated, particularly in pediatrics where the need for improved non-invasive diagnostic and monitoring methods is most urgent. This work presents the first formal evidence-based judgment of the clinical potential of breath volatilome in the pediatric population. METHODS A rigorous systematic review across Web of Science, SCOPUS, and PubMed databases following the PRISMA statement guidelines. A narrative synthesis of the evidence was conducted and QUADAS-2 was used to assess the quality of selected studies. RESULTS Two independent reviewers deemed 22 out of the 229 records initially found to satisfy inclusion criteria. A summary of breath VOCs found to be relevant for several respiratory, infectious, and metabolic pathologies was conducted. In addition, we assessed their associated metabolism coverage through a functional characterization analysis. CONCLUSION Our results indicate that current research remains stagnant in a preclinical exploratory setting. Designing exploratory experiments in compliance with metabolomics practice should drive forward the clinical translation of VOCs breath analysis. IMPACT What is the key message of your article? Metabolomics practice could help to achieve the clinical utility of exhaled volatilome analysis. What does it add to the existing literature? This work is the first systematic review focused on disease status discrimination using analysis of exhaled breath in the pediatric population. A summary of the reported exhaled volatile organic compounds is conducted together with a functional characterization analysis. What is the impact? Having noted challenges preventing the clinical translation, we summary metabolomics practices and the experimental designs that are closer to clinical practice to create a framework to guide future trials.
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Affiliation(s)
- Rosa A Sola Martínez
- Department of Biochemistry and Molecular Biology (B) and Immunology, University of Murcia and Murcian Institute of Biosanitary Research Virgen de la Arrixaca (IMIB), Murcia, Spain
| | - José M Pastor Hernández
- Department of Biochemistry and Molecular Biology (B) and Immunology, University of Murcia and Murcian Institute of Biosanitary Research Virgen de la Arrixaca (IMIB), Murcia, Spain
| | - Óscar Yanes Torrado
- Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.,Institut d'Investigació Sanitària Pere Virgili (IISPV), Metabolomics Platform, Reus, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Cánovas Díaz
- Department of Biochemistry and Molecular Biology (B) and Immunology, University of Murcia and Murcian Institute of Biosanitary Research Virgen de la Arrixaca (IMIB), Murcia, Spain
| | - Teresa de Diego Puente
- Department of Biochemistry and Molecular Biology (B) and Immunology, University of Murcia and Murcian Institute of Biosanitary Research Virgen de la Arrixaca (IMIB), Murcia, Spain.
| | - María Vinaixa Crevillent
- Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.,Institut d'Investigació Sanitària Pere Virgili (IISPV), Metabolomics Platform, Reus, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
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20
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Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment. Metabolites 2021; 11:metabo11040251. [PMID: 33919626 PMCID: PMC8072856 DOI: 10.3390/metabo11040251] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/07/2021] [Accepted: 04/15/2021] [Indexed: 12/16/2022] Open
Abstract
Asthma in children remains a significant public health challenge affecting 5–20% of children in Europe and is associated with increased morbidity and societal healthcare costs. The high variation in asthma incidence among countries may be attributed to differences in genetic susceptibility and environmental factors. This respiratory disorder is described as a heterogeneous syndrome of multiple clinical manifestations (phenotypes) with varying degrees of severity and airway hyper-responsiveness, which is based on patient symptoms, lung function and response to pharmacotherapy. However, an accurate diagnosis is often difficult due to diversities in clinical presentation. Therefore, identifying early diagnostic biomarkers and improving the monitoring of airway dysfunction and inflammatory through non-invasive methods are key goals in successful pediatric asthma management. Given that asthma is caused by the interaction between genes and environmental factors, an emerging approach, metabolomics—the systematic analysis of small molecules—can provide more insight into asthma pathophysiological mechanisms, enable the identification of early biomarkers and targeted personalized therapies, thus reducing disease burden and societal cost. The purpose of this review is to present evidence on the utility of metabolomics in pediatric asthma through the analysis of intermediate metabolites of biochemical pathways that involve carbohydrates, amino acids, lipids, organic acids and nucleotides and discuss their potential application in clinical practice. Also, current challenges on the integration of metabolomics in pediatric asthma management and needed next steps are critically discussed.
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21
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Elenius V, Chawes B, Malmberg PL, Adamiec A, Ruszczyński M, Feleszko W, Jartti T. Lung function testing and inflammation markers for wheezing preschool children: A systematic review for the EAACI Clinical Practice Recommendations on Diagnostics of Preschool Wheeze. Pediatr Allergy Immunol 2021; 32:501-513. [PMID: 33222297 DOI: 10.1111/pai.13418] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 11/06/2020] [Accepted: 11/13/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND Preschool wheeze is highly prevalent; 30%-50% of children have wheezed at least once before age six. Wheezing is not a disorder; it is a symptom of obstruction in the airways, and it is essential to identify the correct diagnosis behind this symptom. An increasing number of studies provide evidence for novel diagnostic tools for monitoring and predicting asthma in the pediatric population. Several techniques are available to measure airway obstruction and airway inflammation, including spirometry, impulse oscillometry, whole-body plethysmography, bronchial hyperresponsiveness test, multiple breath washout test, measurements of exhaled NO, and analyses of various other biomarkers. METHODS We systematically reviewed all the existing techniques available for measuring lung function and airway inflammation in preschool children to assess their potential and clinical value in the routine diagnostics and monitoring of airway obstruction. RESULTS If applicable, measuring FEV1 using spirometry is considered useful. For those unable to perform spirometry, whole-body plethysmography and IOS may be useful. Bronchial reversibility to beta2-agonist and hyperresponsiveness test with running exercise challenge may improve the sensitivity of these tests. CONCLUSIONS The difficulty of measuring lung function and the lack of large randomized controlled trials makes it difficult to establish guidelines for monitoring asthma in preschool children.
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Affiliation(s)
- Varpu Elenius
- Department of Pediatrics, Turku University Hospital and Turku University, Turku, Finland
| | - Bo Chawes
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Pekka L Malmberg
- The Skin and Allergy Hospital, University of Helsinki, Helsinki, Finland
| | - Aleksander Adamiec
- Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland.,Department of Pediatric Pneumology and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Marek Ruszczyński
- Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland
| | - Wojciech Feleszko
- Department of Pediatric Pneumology and Allergy, Medical University of Warsaw, Warsaw, Poland
| | - Tuomas Jartti
- Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
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22
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Monedeiro F, Monedeiro-Milanowski M, Ratiu IA, Brożek B, Ligor T, Buszewski B. Needle Trap Device-GC-MS for Characterization of Lung Diseases Based on Breath VOC Profiles. Molecules 2021; 26:molecules26061789. [PMID: 33810121 PMCID: PMC8004837 DOI: 10.3390/molecules26061789] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 01/08/2023] Open
Abstract
Volatile organic compounds (VOCs) have been assessed in breath samples as possible indicators of diseases. The present study aimed to quantify 29 VOCs (previously reported as potential biomarkers of lung diseases) in breath samples collected from controls and individuals with lung cancer, chronic obstructive pulmonary disease and asthma. Besides that, global VOC profiles were investigated. A needle trap device (NTD) was used as pre-concentration technique, associated to gas chromatography-mass spectrometry (GC-MS) analysis. Univariate and multivariate approaches were applied to assess VOC distributions according to the studied diseases. Limits of quantitation ranged from 0.003 to 6.21 ppbv and calculated relative standard deviations did not exceed 10%. At least 15 of the quantified targets presented themselves as discriminating features. A random forest (RF) method was performed in order to classify enrolled conditions according to VOCs' latent patterns, considering VOCs responses in global profiles. The developed model was based on 12 discriminating features and provided overall balanced accuracy of 85.7%. Ultimately, multinomial logistic regression (MLR) analysis was conducted using the concentration of the nine most discriminative targets (2-propanol, 3-methylpentane, (E)-ocimene, limonene, m-cymene, benzonitrile, undecane, terpineol, phenol) as input and provided an average overall accuracy of 95.5% for multiclass prediction.
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Affiliation(s)
- Fernanda Monedeiro
- Interdisciplinary Centre of Modern Technologies, Nicolaus Copernicus University in Toruń, 4 Wileńska St., 87-100 Toruń, Poland; (F.M.); (M.M.-M.); (I.-A.R.); (B.B.)
| | - Maciej Monedeiro-Milanowski
- Interdisciplinary Centre of Modern Technologies, Nicolaus Copernicus University in Toruń, 4 Wileńska St., 87-100 Toruń, Poland; (F.M.); (M.M.-M.); (I.-A.R.); (B.B.)
| | - Ileana-Andreea Ratiu
- Interdisciplinary Centre of Modern Technologies, Nicolaus Copernicus University in Toruń, 4 Wileńska St., 87-100 Toruń, Poland; (F.M.); (M.M.-M.); (I.-A.R.); (B.B.)
- “Raluca Ripan” Institute for Research in Chemistry, Babeş-Bolyai University, 30 Fântânele St., RO-400294 Cluj-Napoca, Romania
- Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, 7 Gagarina St., 87-100 Toruń, Poland
| | - Beata Brożek
- Department of Lung Diseases, Provincial Polyclinic Hospital in Toruń, 4 Krasińskiego St., 87-100 Toruń, Poland;
| | - Tomasz Ligor
- Interdisciplinary Centre of Modern Technologies, Nicolaus Copernicus University in Toruń, 4 Wileńska St., 87-100 Toruń, Poland; (F.M.); (M.M.-M.); (I.-A.R.); (B.B.)
- Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, 7 Gagarina St., 87-100 Toruń, Poland
- Correspondence: ; Tel.: +48-(56)-665-60-58
| | - Bogusław Buszewski
- Interdisciplinary Centre of Modern Technologies, Nicolaus Copernicus University in Toruń, 4 Wileńska St., 87-100 Toruń, Poland; (F.M.); (M.M.-M.); (I.-A.R.); (B.B.)
- Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, 7 Gagarina St., 87-100 Toruń, Poland
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23
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Ophelders DRMG, Boots AW, Hütten MC, Al-Nasiry S, Jellema RK, Spiller OB, van Schooten FJ, Smolinska A, Wolfs TGAM. Screening of Chorioamnionitis Using Volatile Organic Compound Detection in Exhaled Breath: A Pre-clinical Proof of Concept Study. Front Pediatr 2021; 9:617906. [PMID: 34123958 PMCID: PMC8187797 DOI: 10.3389/fped.2021.617906] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/29/2021] [Indexed: 11/13/2022] Open
Abstract
Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamical changes of organ injury after the onset of chorioamnionitis revealed novel therapeutic windows of opportunity. Importantly, successful development and implementation of therapies in clinical care is currently impeded by a lack of diagnostic tools for early (prenatal) detection and surveillance of intra-amniotic infections. In the current study we questioned whether an intra-amniotic infection could be accurately diagnosed by a specific volatile organic compound (VOC) profile in exhaled breath of pregnant sheep. For this purpose pregnant Texel ewes were inoculated intra-amniotically with Ureaplasma parvum and serial collections of exhaled breath were performed for 6 days. Ureaplasma parvum infection induced a distinct VOC-signature in expired breath of pregnant sheep that was significantly different between day 0 and 1 vs. day 5 and 6. Based on a profile of only 15 discriminatory volatiles, animals could correctly be classified as either infected (day 5 and 6) or not (day 0 and 1) with a sensitivity of 83% and a specificity of 71% and an area under the curve of 0.93. Chemical identification of these distinct VOCs revealed the presence of a lipid peroxidation marker nonanal and various hydrocarbons including n-undecane and n-dodecane. These data indicate that intra-amniotic infections can be detected by VOC analyses of exhaled breath and might provide insight into temporal dynamics of intra-amniotic infection and its underlying pathways. In particular, several of these volatiles are associated with enhanced oxidative stress and undecane and dodecane have been reported as predictive biomarker of spontaneous preterm birth in humans. Applying VOC analysis for the early detection of intra-amniotic infections will lead to appropriate surveillance of these high-risk pregnancies, thereby facilitating appropriate clinical course of action including early treatment of preventative measures for pre-maturity-associated morbidities.
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Affiliation(s)
- Daan R M G Ophelders
- Department of Pediatrics, Maastricht University Medical Center+, Maastricht, Netherlands.,GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Agnes W Boots
- Department Pharmacology and Toxicology, Maastricht University, Maastricht, Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Matthias C Hütten
- Department of Pediatrics, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Salwan Al-Nasiry
- GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Department of Obstetrics and Gynecology, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Reint K Jellema
- Department of Pediatrics, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Owen B Spiller
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Frederik-Jan van Schooten
- Department Pharmacology and Toxicology, Maastricht University, Maastricht, Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Agnieszka Smolinska
- Department Pharmacology and Toxicology, Maastricht University, Maastricht, Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Tim G A M Wolfs
- Department of Pediatrics, Maastricht University Medical Center+, Maastricht, Netherlands.,GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
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24
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Holden K, Makinde M, Wilde M, Richardson M, Coats T, Monks P, Gaillard EA. Assessing the feasibility and acceptability of online measurements of exhaled volatile organic compounds (VOCs) in children with preschool wheeze: a pilot study. BMJ Paediatr Open 2021; 5:e001003. [PMID: 34568587 PMCID: PMC8438855 DOI: 10.1136/bmjpo-2020-001003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/17/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Investigating airway inflammation and pathology in wheezy preschool children is both technically and ethically challenging. Identifying and validating non-invasive tests would be a huge clinical advance. Real-time analysis of exhaled volatile organic compounds (VOCs) in adults is established, however, the feasibility of this non-invasive method in young children remains undetermined. AIM To determine the feasibility and acceptability of obtaining breath samples from preschool children by means of real-time mass spectrometry analysis of exhaled VOCs. METHODS Breath samples from preschool children were collected and analysed in real time by proton transfer reaction-time of flight-mass spectrometry (PTR-TOF-MS) capturing unique breath profiles. Acetone (mass channel m/z 59) was used as a reference profile to investigate the breath cycle in more detail. Dynamic time warping (DTW) was used to compare VOC profiles from adult breath to those we obtained in preschool children. RESULTS 16 children were recruited in the study, of which eight had acute doctor-diagnosed wheeze (mean (range) age 3.2 (1.9-4.5) years) and eight had no history of wheezing (age 3.3 (2.2-4.1) years). Fully analysable samples were obtained in 11 (68%). DTW was used to ascertain the distance between the time series of mass channel m/z 59 (acetone) and the other 193 channels. Commonality of 12 channels (15, 31, 33, 41, 43, 51, 53, 55, 57, 60, 63 and 77) was established between adult and preschool child samples despite differences in the breathing patterns. CONCLUSION Real-time measurement of exhaled VOCs by means of PTR-MS is feasible and acceptable in preschool children. Commonality in VOC profiles was found between adult and preschool children.
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Affiliation(s)
- Karl Holden
- Leicester NIHR Biomedical Research Centre (Respiratory Theme), Glenfield Hospital, Leicester, UK.,Department of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester, UK
| | - Misty Makinde
- Leicester NIHR Biomedical Research Centre (Respiratory Theme), Glenfield Hospital, Leicester, UK.,Department of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester, UK
| | - Michael Wilde
- Department of Chemistry, University of Leicester, Leicester, UK
| | - Matthew Richardson
- Leicester NIHR Biomedical Research Centre (Respiratory Theme), Glenfield Hospital, Leicester, UK.,Department of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester, UK
| | - Tim Coats
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Paul Monks
- Department of Chemistry, University of Leicester, Leicester, UK
| | - Erol A Gaillard
- Leicester NIHR Biomedical Research Centre (Respiratory Theme), Glenfield Hospital, Leicester, UK.,Department of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester, UK
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25
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Grassin-Delyle S, Roquencourt C, Moine P, Saffroy G, Carn S, Heming N, Fleuriet J, Salvator H, Naline E, Couderc LJ, Devillier P, Thévenot EA, Annane D. Metabolomics of exhaled breath in critically ill COVID-19 patients: A pilot study. EBioMedicine 2021; 63:103154. [PMID: 33279860 PMCID: PMC7714658 DOI: 10.1016/j.ebiom.2020.103154] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/06/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Early diagnosis of coronavirus disease 2019 (COVID-19) is of the utmost importance but remains challenging. The objective of the current study was to characterize exhaled breath from mechanically ventilated adults with COVID-19. METHODS In this prospective observational study, we used real-time, online, proton transfer reaction time-of-flight mass spectrometry to perform a metabolomic analysis of expired air from adults undergoing invasive mechanical ventilation in the intensive care unit due to severe COVID-19 or non-COVID-19 acute respiratory distress syndrome (ARDS). FINDINGS Between March 25th and June 25th, 2020, we included 40 patients with ARDS, of whom 28 had proven COVID-19. In a multivariate analysis, we identified a characteristic breathprint for COVID-19. We could differentiate between COVID-19 and non-COVID-19 ARDS with accuracy of 93% (sensitivity: 90%, specificity: 94%, area under the receiver operating characteristic curve: 0·94-0·98, after cross-validation). The four most prominent volatile compounds in COVID-19 patients were methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal. INTERPRETATION The real-time, non-invasive detection of methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal in exhaled breath may identify ARDS patients with COVID-19. FUNDING The study was funded by Agence Nationale de la Recherche (SoftwAiR, ANR-18-CE45-0017 and RHU4 RECORDS, Programme d'Investissements d'Avenir, ANR-18-RHUS-0004), Région Île de France (SESAME 2016), and Fondation Foch.
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Affiliation(s)
- Stanislas Grassin-Delyle
- Hôpital Foch, Exhalomics®, Département des maladies des voies respiratoires, Suresnes, France (S.G.D., H.S., E.N., L-J.C., P.D.); Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, Montigny le Bretonneux, France (S.G.D., P.M., N.H., D.A.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)..
| | - Camille Roquencourt
- CEA, LIST, Laboratoire Sciences des Données et de la Décision, Gif-sur-Yvette, France (C.R.)
| | - Pierre Moine
- Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, Montigny le Bretonneux, France (S.G.D., P.M., N.H., D.A.); Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.)
| | - Gabriel Saffroy
- Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.)
| | - Stanislas Carn
- Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.)
| | - Nicholas Heming
- Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, Montigny le Bretonneux, France (S.G.D., P.M., N.H., D.A.); Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.)
| | - Jérôme Fleuriet
- Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.)
| | - Hélène Salvator
- Hôpital Foch, Exhalomics®, Département des maladies des voies respiratoires, Suresnes, France (S.G.D., H.S., E.N., L-J.C., P.D.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)
| | - Emmanuel Naline
- Hôpital Foch, Exhalomics®, Département des maladies des voies respiratoires, Suresnes, France (S.G.D., H.S., E.N., L-J.C., P.D.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)
| | - Louis-Jean Couderc
- Hôpital Foch, Exhalomics®, Département des maladies des voies respiratoires, Suresnes, France (S.G.D., H.S., E.N., L-J.C., P.D.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)
| | - Philippe Devillier
- Hôpital Foch, Exhalomics®, Département des maladies des voies respiratoires, Suresnes, France (S.G.D., H.S., E.N., L-J.C., P.D.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)
| | - Etienne A Thévenot
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, MetaboHUB, Gif-sur-Yvette, France (E.T.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)
| | - Djillali Annane
- Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, Montigny le Bretonneux, France (S.G.D., P.M., N.H., D.A.); Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.)
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26
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Data preprocessing workflow for exhaled breath analysis by GC/MS using open sources. Sci Rep 2020; 10:22008. [PMID: 33319832 PMCID: PMC7738550 DOI: 10.1038/s41598-020-79014-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/03/2020] [Indexed: 12/24/2022] Open
Abstract
The noninvasive diagnosis and monitoring of high prevalence diseases such as cardiovascular diseases, cancers and chronic respiratory diseases are currently priority objectives in the area of health. In this regard, the analysis of volatile organic compounds (VOCs) has been identified as a potential noninvasive tool for the diagnosis and surveillance of several diseases. Despite the advantages of this strategy, it is not yet a routine clinical tool. The lack of reproducible protocols for each step of the biomarker discovery phase is an obstacle of the current state. Specifically, this issue is present at the data preprocessing step. Thus, an open source workflow for preprocessing the data obtained by the analysis of exhaled breath samples using gas chromatography coupled with single quadrupole mass spectrometry (GC/MS) is presented in this paper. This workflow is based on the connection of two approaches to transform raw data into a useful matrix for statistical analysis. Moreover, this workflow includes matching compounds from breath samples with a spectral library. Three free packages (xcms, cliqueMS and eRah) written in the language R are used for this purpose. Furthermore, this paper presents a suitable protocol for exhaled breath sample collection from infants under 2 years of age for GC/MS.
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Peltrini R, Cordell R, Ibrahim W, Wilde M, Salman D, Singapuri A, Hargadon B, Brightling CE, Thomas CLP, Monks P, Siddiqui S. Volatile organic compounds in a headspace sampling system and asthmatics sputum samples. J Breath Res 2020; 15. [PMID: 33227714 DOI: 10.1088/1752-7163/abcd2a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/23/2020] [Indexed: 12/17/2022]
Abstract
Background:The headspace of a biological sample contains exogenous VOCs present within the sampling environment which represent the background signal.Study aims:This study aimed to characterise the background signal generated from a headspace sampling system in a clinical site, to evaluate intra- and inter-day variation of background VOC and to understand the impact of a sample itself upon commonly reported background VOC using sputum headspace samples from severe asthmatics.Methods:The headspace, in absence of a biological sample, was collected hourly from 11am to 3pm within a day (time of clinical samples acquisition), and from Monday to Friday in a week, and analysed by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Chemometric analysis identified 1120 features, 37 of which were present in at least the 80% of all the samples. The analyses of intra- and inter-day background variations were performed on thirteen of the most abundant features, ubiquitously present in headspace samples. The concentration ratios relative to background were reported for the selected abundant VOC in 36 asthmatic sputum samples, acquired from 36 stable severe asthma patients recruited at Glenfield Hospital, Leicester, UK.Results:The results identified no significant intra- or inter-day variations in compounds levels and no systematic bias of z-scores, with the exclusion of benzothiazole, whose abundance increased linearly between 11am and 3pm with a maximal intra-day fold change of 2.13. Many of the identified background features are reported in literature as components of headspace of biological samples and are considered potential biomarkers for several diseases. The selected background features were identified in headspace of all severe asthma sputum samples, albeit with varying levels of enrichment relative to background.Conclusion:Our observations support the need to consider the background signal derived from the headspace sampling system when developing and validating headspace biomarker signatures using clinical samples.
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Affiliation(s)
- Rosa Peltrini
- University of Leicester College of Life Sciences, Leicester, LE1 9HN, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Rebecca Cordell
- Chemistry department, University of Leicester, Leicester, Leicestershire, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Wadah Ibrahim
- University of Leicester College of Life Sciences, Leicester, Leicester, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Michael Wilde
- Chemistry department, University of Leicester, Leicester, Leicestershire, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Dahlia Salman
- Chemistry, Loughborough University School of Science, Loughborough, LE11 3TU, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Amisha Singapuri
- University of Leicester, Leicester, Leicestershire, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Beverley Hargadon
- University of Leicester, Leicester, Leicestershire, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Christopher E Brightling
- University of Leicester, Leicester, Leicestershire, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - C L Paul Thomas
- Department of Chemistry, Centre for Analytical Science, Loughborough University School of Science, LOUGHBOROUGH, Leicestershire, LE11 3TU, Loughborough, LE11 3TU, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Paul Monks
- Chemistry department, University of Leicester, Leicester, Leicestershire, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Salman Siddiqui
- University of Leicester College of Life Sciences, Leicester, Leicester, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
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Fuchsmann P, Tena Stern M, Münger LH, Pimentel G, Burton KJ, Vionnet N, Vergères G. Nutrivolatilomics of Urinary and Plasma Samples to Identify Candidate Biomarkers after Cheese, Milk, and Soy-Based Drink Intake in Healthy Humans. J Proteome Res 2020; 19:4019-4033. [DOI: 10.1021/acs.jproteome.0c00324] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
| | | | | | | | | | - Nathalie Vionnet
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland
| | - Guy Vergères
- Agroscope, Schwarzenburgstrasse 161, 3003 Bern, Switzerland
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29
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Sarandi E, Thanasoula M, Anamaterou C, Papakonstantinou E, Geraci F, Papamichael MM, Itsiopoulos C, Tsoukalas D. Metabolic profiling of organic and fatty acids in chronic and autoimmune diseases. Adv Clin Chem 2020; 101:169-229. [PMID: 33706889 DOI: 10.1016/bs.acc.2020.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Metabolomics is a powerful tool of omics that permits the simultaneous identification of metabolic perturbations in several autoimmune and chronic diseases. Several parameters can affect a metabolic profile, from the population characteristics to the selection of the analytical method. In the current chapter, we summarize the main analytical methods and results of the metabolic profiling of fatty and organic acids performed in human metabolomic studies for asthma, COPD, psoriasis and Hashimoto's thyroiditis. We discuss the most significant metabolic alterations associated with these diseases, after comparison of either a single patient's group with healthy controls or several patient's subgroups of different disease severity and phenotype with healthy controls or of a patient's group before and after treatment. Finally, we present critical metabolic patterns that are associated with each disease and their potency for the unraveling of disease pathogenesis, prediction, diagnosis, patient stratification and treatment selection.
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Affiliation(s)
- Evangelia Sarandi
- Metabolomic Medicine Clinic, Athens, Greece; Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, Heraklion, Greece
| | - Maria Thanasoula
- Metabolomic Medicine Clinic, Athens, Greece; European Institute of Nutritional Medicine, E.I.Nu.M, Rome, Italy
| | | | | | - Francesco Geraci
- European Institute of Nutritional Medicine, E.I.Nu.M, Rome, Italy
| | - Maria Michelle Papamichael
- Department of Rehabilitation, Nutrition & Sport, La Trobe University, School of Allied Health, Melbourne, VIC, Australia
| | - Catherine Itsiopoulos
- Department of Rehabilitation, Nutrition & Sport, La Trobe University, School of Allied Health, Melbourne, VIC, Australia
| | - Dimitris Tsoukalas
- Metabolomic Medicine Clinic, Athens, Greece; European Institute of Nutritional Medicine, E.I.Nu.M, Rome, Italy.
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30
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Sadeghi-Yarandi M, Golbabaei F, Karimi A. Evaluation of pulmonary function and respiratory symptoms among workers exposed to 1,3-Butadiene in a petrochemical industry in Iran. ARCHIVES OF ENVIRONMENTAL & OCCUPATIONAL HEALTH 2020; 75:483-490. [PMID: 32338162 DOI: 10.1080/19338244.2020.1749018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
This study aimed to evaluate pulmonary function among workers exposed to 1,3-butadiene and was carried out in a petrochemical industry in Iran. The study participants consisted of fifty male workers with current respiratory exposure to 1,3-butadiene and fifty non-exposed workers as the control group. Exposure to 1,3-butadiene was measured according to the NIOSH 1024 method. Respiratory symptom histories were collected through the American Thoracic Society respiratory symptom questionnaire. Lung functions were evaluated using spirometry method. The results showed that exposed participants had significantly higher prevalence rates of all respiratory symptoms compared to the control group. Statistical tests demonstrated a significant difference between pulmonary function tests of exposed and non-exposed personnel. Ultimately, the results of the present study indicate that respiratory exposure to 1,3-butadiene can lead to negative effects on pulmonary functions.
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Affiliation(s)
- Mohsen Sadeghi-Yarandi
- Department of Occupational Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Golbabaei
- Department of Occupational Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Karimi
- Department of Occupational Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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31
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Parisi GF, Papale M, Tardino L, Nenna R, Midulla F, Leonardi S. Biomarkers in Pediatric Lung Diseases Including Cystic Fibrosis. CURRENT RESPIRATORY MEDICINE REVIEWS 2020. [DOI: 10.2174/1573398x15666190521112824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In recent decades, scientific studies of chemical processes involving metabolites have been
steadily increasing, indicating that we are well into the metabolomics era. This has resulted in
numerous studies that explore the field of biomarkers. One of the medical areas most concerned with
these innovations is certainly that of childhood respiratory disorders, including asthma and cystic
fibrosis. This current study is a review of the literature about biomarkers used or studied in the field
of pediatric pulmonology, including asthma and cystic fibrosis.
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Affiliation(s)
- Giuseppe Fabio Parisi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Maria Papale
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Lucia Tardino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Raffaella Nenna
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Fabio Midulla
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
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32
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Bruderer T, Gaisl T, Gaugg MT, Nowak N, Streckenbach B, Müller S, Moeller A, Kohler M, Zenobi R. On-Line Analysis of Exhaled Breath Focus Review. Chem Rev 2019; 119:10803-10828. [PMID: 31594311 DOI: 10.1021/acs.chemrev.9b00005] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
On-line analysis of exhaled breath offers insight into a person's metabolism without the need for sample preparation or sample collection. Due to its noninvasive nature and the possibility to sample continuously, the analysis of breath has great clinical potential. The unique features of this technology make it an attractive candidate for applications in medicine, beyond the task of diagnosis. We review the current methodologies for on-line breath analysis, discuss current and future applications, and critically evaluate challenges and pitfalls such as the need for standardization. Special emphasis is given to the use of the technology in diagnosing respiratory diseases, potential niche applications, and the promise of breath analysis for personalized medicine. The analytical methodologies used range from very small and low-cost chemical sensors, which are ideal for continuous monitoring of disease status, to optical spectroscopy and state-of-the-art, high-resolution mass spectrometry. The latter can be utilized for untargeted analysis of exhaled breath, with the capability to identify hitherto unknown molecules. The interpretation of the resulting big data sets is complex and often constrained due to a limited number of participants. Even larger data sets will be needed for assessing reproducibility and for validation of biomarker candidates. In addition, molecular structures and quantification of compounds are generally not easily available from on-line measurements and require complementary measurements, for example, a separation method coupled to mass spectrometry. Furthermore, a lack of standardization still hampers the application of the technique to screen larger cohorts of patients. This review summarizes the present status and continuous improvements of the principal on-line breath analysis methods and evaluates obstacles for their wider application.
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Affiliation(s)
- Tobias Bruderer
- Department of Chemistry and Applied Biosciences , Swiss Federal Institute of Technology , CH-8093 Zurich , Switzerland.,Division of Respiratory Medicine , University Children's Hospital Zurich and Children's Research Center Zurich , CH-8032 Zurich , Switzerland
| | - Thomas Gaisl
- Department of Pulmonology , University Hospital Zurich , CH-8091 Zurich , Switzerland.,Zurich Center for Interdisciplinary Sleep Research , University of Zurich , CH-8091 Zurich , Switzerland
| | - Martin T Gaugg
- Department of Chemistry and Applied Biosciences , Swiss Federal Institute of Technology , CH-8093 Zurich , Switzerland
| | - Nora Nowak
- Department of Chemistry and Applied Biosciences , Swiss Federal Institute of Technology , CH-8093 Zurich , Switzerland
| | - Bettina Streckenbach
- Department of Chemistry and Applied Biosciences , Swiss Federal Institute of Technology , CH-8093 Zurich , Switzerland
| | - Simona Müller
- Department of Chemistry and Applied Biosciences , Swiss Federal Institute of Technology , CH-8093 Zurich , Switzerland
| | - Alexander Moeller
- Division of Respiratory Medicine , University Children's Hospital Zurich and Children's Research Center Zurich , CH-8032 Zurich , Switzerland
| | - Malcolm Kohler
- Department of Pulmonology , University Hospital Zurich , CH-8091 Zurich , Switzerland.,Center for Integrative Human Physiology , University of Zurich , CH-8091 Zurich , Switzerland.,Zurich Center for Interdisciplinary Sleep Research , University of Zurich , CH-8091 Zurich , Switzerland
| | - Renato Zenobi
- Department of Chemistry and Applied Biosciences , Swiss Federal Institute of Technology , CH-8093 Zurich , Switzerland
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33
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Lee YJ, Fujisawa T, Kim CK. Biomarkers for Recurrent Wheezing and Asthma in Preschool Children. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2019; 11:16-28. [PMID: 30479074 PMCID: PMC6267183 DOI: 10.4168/aair.2019.11.1.16] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/08/2018] [Accepted: 09/10/2018] [Indexed: 01/21/2023]
Abstract
Wheezing is one of the characteristic symptoms of asthma, but all preschool children with wheezing are not diagnosed with asthma. Preschool children are not cooperative enough to participate in spirometry and invasive tests. Thus, there is no conventional method to diagnose asthma in preschool children. We reviewed studies on non-invasive biomarkers for assessing asthma in preschool children. Specimens that can be easily obtained by non-invasive methods are blood, exhaled breath and urine. Eosinophils, eosinophil cationic protein and eosinophil-derived neurotoxin (EDN) in blood are helpful in evaluating eosinophilic inflammation of the airways. Exhaled breath contains nitric oxide, volatile organic compounds, various cytokines and mediators as analytical components. Fraction of exhaled nitric oxide has been used to assess the degree of eosinophil inflammation and has been standardized in school-age children and adults, but not yet in preschool children. Exhaled breath condensate (EBC) pH and various cytokines/mediators that are detected in EBC seem to be promising biomarkers for assessing asthma, but need more standardization and validation. There are several biomarkers useful for assessing asthma, but none are ideal. Some biomarkers need standardized methods of obtaining samples from uncooperative preschool children for clinical use and require sufficient validation. Recently, another activated eosinophil marker, serum EDN, has shown promising results as a biomarker for recurrent wheezing and asthma in preschool children.
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Affiliation(s)
- Yong Ju Lee
- Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea
| | | | - Chang Keun Kim
- Asthma and Allergy Center, Inje University Sanggye Paik Hospital, Seoul, Korea.,SKIMS-BIO Co., Ltd. Seoul, Korea.
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Fuglsbjerg MG, Rasmussen MA, Hansen KS, Smolinska A, Dallinga JW, van Schooten FJ, Stokholm J, Bønnelykke K, Bisgaard H, Chawes BL. Limited clinical value of exhaled volatile organic compound measurements in childhood asthma. ERJ Open Res 2018; 4:00026-2018. [PMID: 30443556 PMCID: PMC6230817 DOI: 10.1183/23120541.00026-2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 08/01/2018] [Indexed: 12/02/2022] Open
Abstract
Noninvasive, clinically applicable measurements of biomarkers for diagnosis of asthma in early life are needed. We hypothesised that profiles of volatile organic compounds (VOCs) in exhaled breath samples may serve such a purpose. Exhaled volatile organic compound measurements do not aid the clinician diagnosing asthma in childrenhttp://ow.ly/Z2d930lpZ60
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Affiliation(s)
- Maria G Fuglsbjerg
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Morten A Rasmussen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.,Dept of Food Science, Faculty of Science, University of Copenhagen, Denmark
| | - Kirsten S Hansen
- The Pediatric Dept, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Agnieszka Smolinska
- Dept of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Jan W Dallinga
- Dept of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Frederik-Jan van Schooten
- Dept of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Jakob Stokholm
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Bønnelykke
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Hans Bisgaard
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Bo L Chawes
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
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35
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Predicting childhood asthma development: are early life metabolite levels the philosopher's stone to unlock the puzzle? Pediatr Res 2018; 84:593-594. [PMID: 30131594 DOI: 10.1038/s41390-018-0119-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 07/03/2018] [Indexed: 12/16/2022]
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36
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Metwaly S, Cote A, Donnelly SJ, Banoei MM, Mourad AI, Winston BW. Evolution of ARDS biomarkers: Will metabolomics be the answer? Am J Physiol Lung Cell Mol Physiol 2018; 315:L526-L534. [PMID: 29952222 PMCID: PMC7191388 DOI: 10.1152/ajplung.00074.2018] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
To date, there is no clinically agreed-upon diagnostic test for acute respiratory distress syndrome (ARDS): the condition is still diagnosed on the basis of a constellation of clinical findings, laboratory tests, and radiological images. Development of ARDS biomarkers has been in a state of continuous flux during the past four decades. To address ARDS heterogeneity, several studies have recently focused on subphenotyping the disease on the basis of observable clinical characteristics and associated blood biomarkers. However, the strong correlation between identified biomarkers and ARDS subphenotypes has yet to establish etiology; hence, there is a need for the adoption of other methodologies for studying ARDS. In this review, we will shed light on ARDS metabolomics research in the literature and discuss advances and major obstacles encountered in ARDS metabolomics research. Generally, the ARDS metabolomics studies focused on identification of differentiating metabolites for diagnosing ARDS, but they were performed to different standards in terms of sample size, selection of control cohort, type of specimens collected, and measuring technique utilized. Virtually none of these studies have been properly validated to identify true metabolomics biomarkers of ARDS. Though in their infancy, metabolomics studies exhibit promise to unfold the biological processes underlying ARDS and, in our opinion, have great potential for pushing forward our present understanding of ARDS.
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Affiliation(s)
- Sayed Metwaly
- Department of Critical Care Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Andreanne Cote
- Department of Critical Care Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Sarah J Donnelly
- Department of Critical Care Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Mohammad M Banoei
- Department of Critical Care Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Ahmed I Mourad
- Department of Critical Care Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Brent W Winston
- Department of Critical Care Medicine, University of Calgary , Calgary, Alberta , Canada.,Departments of Medicine and Biochemistry and Molecular Biology, University of Calgary , Calgary, Alberta , Canada
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37
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Turi KN, Romick-Rosendale L, Ryckman KK, Hartert TV. A review of metabolomics approaches and their application in identifying causal pathways of childhood asthma. J Allergy Clin Immunol 2018; 141:1191-1201. [PMID: 28479327 PMCID: PMC5671382 DOI: 10.1016/j.jaci.2017.04.021] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 03/08/2017] [Accepted: 04/13/2017] [Indexed: 12/20/2022]
Abstract
Because asthma is a disease that results from host-environment interactions, an approach that allows assessment of the effect of the environment on the host is needed to understand the disease. Metabolomics has appealing potential as an application to study pathways to childhood asthma development. The objective of this review is to provide an overview of metabolomics methods and their application to understanding host-environment pathways in asthma development. We reviewed recent literature on advances in metabolomics and their application to study pathways to childhood asthma development. We highlight the (1) potential of metabolomics in understanding the pathogenesis of disease and the discovery of biomarkers; (2) choice of metabolomics techniques, biospecimen handling, and data analysis; (3) application to studying the role of the environment on asthma development; (4) review of metabolomics applied to the outcome of asthma; (5) recommendations for application of metabolomics-based -omics data integration in understanding disease pathogenesis; and (6) limitations. In conclusion, metabolomics allows use of biospecimens to identify useful biomarkers and pathways involved in disease development and subsequently to inform a greater understanding of disease pathogenesis and endotypes and prediction of the clinical course of childhood asthma phenotypes.
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Affiliation(s)
- Kedir N Turi
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn
| | - Lindsey Romick-Rosendale
- Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kelli K Ryckman
- Departments of Epidemiology and Pediatrics, College of Public Health and Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Tina V Hartert
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
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Peel AM, Wilson AM, Loke YK. Asthma breathomics-promising biomarkers in need of validation. Pediatr Pulmonol 2018; 53:263-265. [PMID: 29359422 DOI: 10.1002/ppul.23941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 12/09/2017] [Indexed: 11/11/2022]
Affiliation(s)
- Adam M Peel
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Andrew M Wilson
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Yoon K Loke
- Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK
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Neerincx AH, Vijverberg SJH, Bos LDJ, Brinkman P, van der Schee MP, de Vries R, Sterk PJ, Maitland-van der Zee AH. Breathomics from exhaled volatile organic compounds in pediatric asthma. Pediatr Pulmonol 2017; 52:1616-1627. [PMID: 29082668 DOI: 10.1002/ppul.23785] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 07/21/2017] [Indexed: 12/19/2022]
Abstract
Asthma is the most common chronic disease in children, and is characterized by airway inflammation, bronchial hyperresponsiveness, and airflow obstruction. Asthma diagnosis, phenotyping, and monitoring are still challenging with currently available methods, such as spirometry, FE NO or sputum analysis. The analysis of volatile organic compounds (VOCs) in exhaled breath could be an interesting non-invasive approach, but has not yet reached clinical practice. This review describes the current status of breath analysis in the diagnosis and monitoring of pediatric asthma. Furthermore, features of an ideal breath test, different breath analysis techniques, and important methodological issues are discussed. Although only a (small) number of studies have been performed in pediatric asthma, of which the majority is focusing on asthma diagnosis, these studies show moderate to good prediction accuracy (80-100%, with models including 6-28 VOCs), thereby qualifying breathomics for future application. However, standardization of procedures, longitudinal studies, as well as external validation are needed in order to further develop breathomics into clinical tools. Such a non-invasive tool may be the next step toward stratified and personalized medicine in pediatric respiratory disease.
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Affiliation(s)
- Anne H Neerincx
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
| | - Susanne J H Vijverberg
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
| | - Lieuwe D J Bos
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands.,Department of Intensive Care Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
| | - Paul Brinkman
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
| | - Marc P van der Schee
- Department of Paediatric Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
| | - Rianne de Vries
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
| | - Peter J Sterk
- Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
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40
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Bowler RP, Wendt CH, Fessler MB, Foster MW, Kelly RS, Lasky-Su J, Rogers AJ, Stringer KA, Winston BW. New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report. Ann Am Thorac Soc 2017; 14:1721-1743. [PMID: 29192815 PMCID: PMC5946579 DOI: 10.1513/annalsats.201710-770ws] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
This document presents the proceedings from the workshop entitled, "New Strategies and Challenges in Lung Proteomics and Metabolomics" held February 4th-5th, 2016, in Denver, Colorado. It was sponsored by the National Heart Lung Blood Institute, the American Thoracic Society, the Colorado Biological Mass Spectrometry Society, and National Jewish Health. The goal of this workshop was to convene, for the first time, relevant experts in lung proteomics and metabolomics to discuss and overcome specific challenges in these fields that are unique to the lung. The main objectives of this workshop were to identify, review, and/or understand: (1) emerging technologies in metabolomics and proteomics as applied to the study of the lung; (2) the unique composition and challenges of lung-specific biological specimens for metabolomic and proteomic analysis; (3) the diverse informatics approaches and databases unique to metabolomics and proteomics, with special emphasis on the lung; (4) integrative platforms across genetic and genomic databases that can be applied to lung-related metabolomic and proteomic studies; and (5) the clinical applications of proteomics and metabolomics. The major findings and conclusions of this workshop are summarized at the end of the report, and outline the progress and challenges that face these rapidly advancing fields.
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Horváth I, Barnes PJ, Loukides S, Sterk PJ, Högman M, Olin AC, Amann A, Antus B, Baraldi E, Bikov A, Boots AW, Bos LD, Brinkman P, Bucca C, Carpagnano GE, Corradi M, Cristescu S, de Jongste JC, Dinh-Xuan AT, Dompeling E, Fens N, Fowler S, Hohlfeld JM, Holz O, Jöbsis Q, Van De Kant K, Knobel HH, Kostikas K, Lehtimäki L, Lundberg J, Montuschi P, Van Muylem A, Pennazza G, Reinhold P, Ricciardolo FLM, Rosias P, Santonico M, van der Schee MP, van Schooten FJ, Spanevello A, Tonia T, Vink TJ. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J 2017; 49:49/4/1600965. [PMID: 28446552 DOI: 10.1183/13993003.00965-2016] [Citation(s) in RCA: 403] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 01/09/2017] [Indexed: 12/19/2022]
Abstract
Breath tests cover the fraction of nitric oxide in expired gas (FeNO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FeNO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FeNO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.
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Affiliation(s)
- Ildiko Horváth
- Dept of Pulmonology, National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Peter J Barnes
- National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, London, UK
| | | | - Peter J Sterk
- Dept of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Marieann Högman
- Centre for Research & Development, Uppsala University/Gävleborg County Council, Gävle, Sweden
| | - Anna-Carin Olin
- Occupational and Environmental Medicine, Sahlgrenska Academy and University Hospital, Goteborg, Sweden
| | - Anton Amann
- Innsbruck Medical University, Innsbruck, Austria
| | - Balazs Antus
- Dept of Pathophysiology, National Korányi Institute of Pulmonology, Budapest, Hungary
| | | | - Andras Bikov
- Dept of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Agnes W Boots
- Dept of Pharmacology and Toxicology, University of Maastricht, Maastricht, The Netherlands
| | - Lieuwe D Bos
- Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Paul Brinkman
- Dept of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Caterina Bucca
- Biomedical Sciences and Human Oncology, Universita' di Torino, Turin, Italy
| | | | | | - Simona Cristescu
- Dept of Molecular and Laser Physics, Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands
| | - Johan C de Jongste
- Dept of Pediatrics/Respiratory Medicine, Erasmus MC-Sophia Childrens' Hospital, Rotterdam, The Netherlands
| | | | - Edward Dompeling
- Dept of Paediatrics/Family Medicine Research School CAPHRI, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Niki Fens
- Dept of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Stephen Fowler
- Respiratory Research Group, University of Manchester Wythenshawe Hospital, Manchester, UK
| | - Jens M Hohlfeld
- Clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany.,Medizinische Hochschule Hannover, Hannover, Germany
| | - Olaf Holz
- Clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany
| | - Quirijn Jöbsis
- Department of Paediatric Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Kim Van De Kant
- Dept of Paediatrics/Family Medicine Research School CAPHRI, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Hugo H Knobel
- Philips Research, High Tech Campus 11, Eindhoven, The Netherlands
| | | | | | - Jon Lundberg
- Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Paolo Montuschi
- Pharmacology, Catholic University of the Sacred Heart, Rome, Italy
| | - Alain Van Muylem
- Hopital Erasme Cliniques Universitaires de Bruxelles, Bruxelles, Belgium
| | - Giorgio Pennazza
- Faculty of Engineering, University Campus Bio-Medico, Rome, Italy
| | - Petra Reinhold
- Institute of Molecular Pathogenesis, Friedrich Loeffler Institut, Jena, Germany
| | - Fabio L M Ricciardolo
- Clinic of Respiratory Disease, Dept of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Philippe Rosias
- Dept of Paediatrics/Family Medicine Research School CAPHRI, Maastricht University Medical Centre, Maastricht, The Netherlands.,Dept of Pediatrics, Maasland Hospital, Sittard, The Netherlands
| | - Marco Santonico
- Faculty of Engineering, University Campus Bio-Medico, Rome, Italy
| | - Marc P van der Schee
- Dept of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | | | | | - Thomy Tonia
- European Respiratory Society, Lausanne, Switzerland
| | - Teunis J Vink
- Philips Research, High Tech Campus 11, Eindhoven, The Netherlands
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Lawal O, Ahmed WM, Nijsen TME, Goodacre R, Fowler SJ. Exhaled breath analysis: a review of 'breath-taking' methods for off-line analysis. Metabolomics 2017; 13:110. [PMID: 28867989 PMCID: PMC5563344 DOI: 10.1007/s11306-017-1241-8] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 07/24/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The potential of exhaled breath sampling and analysis has long attracted interest in the areas of medical diagnosis and disease monitoring. This interest is attributed to its non-invasive nature, access to an unlimited sample supply (i.e., breath), and the potential to facilitate a rapid at patient diagnosis. However, progress from laboratory setting to routine clinical practice has been slow. Different methodologies of breath sampling, and the consequent difficulty in comparing and combining data, are considered to be a major contributor to this. To fulfil the potential of breath analysis within clinical and pre-clinical medicine, standardisation of some approaches to breath sampling and analysis will be beneficial. OBJECTIVES The aim of this review is to investigate the heterogeneity of breath sampling methods by performing an in depth bibliometric search to identify the current state of art in the area. In addition, the review will discuss and critique various breath sampling methods for off-line breath analysis. METHODS Literature search was carried out in databases MEDLINE, BIOSIS, EMBASE, INSPEC, COMPENDEX, PQSCITECH, and SCISEARCH using the STN platform which delivers peer-reviewed articles. Keywords searched for include breath, sampling, collection, pre-concentration, volatile. Forward and reverse search was then performed on initially included articles. The breath collection methodologies of all included articles was subsequently reviewed. RESULTS Sampling methods differs between research groups, for example regarding the portion of breath being targeted. Definition of late expiratory breath varies between studies. CONCLUSIONS Breath analysis is an interdisciplinary field of study using clinical, analytical chemistry, data processing, and metabolomics expertise. A move towards standardisation in breath sampling is currently being promoted within the breath research community with a view to harmonising analysis and thereby increasing robustness and inter-laboratory comparisons.
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Affiliation(s)
- Oluwasola Lawal
- 0000000121662407grid.5379.8Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 0000 0004 0398 9387grid.417284.cPhilips Research, Royal Philips B.V., Eindhoven, The Netherlands
- 0000000121662407grid.5379.8School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Waqar M. Ahmed
- 0000000121662407grid.5379.8Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 0000 0004 0398 9387grid.417284.cPhilips Research, Royal Philips B.V., Eindhoven, The Netherlands
- 0000000121662407grid.5379.8School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Tamara M. E. Nijsen
- 0000 0004 0398 9387grid.417284.cPhilips Research, Royal Philips B.V., Eindhoven, The Netherlands
| | - Royston Goodacre
- 0000000121662407grid.5379.8School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK
| | - Stephen J. Fowler
- 0000000121662407grid.5379.8Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 0000 0004 0430 9363grid.5465.2Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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Abstract
Several topics on childhood asthma were addressed in the Paediatric Clinical Year in Review session at the 2015 European Respiratory Society International Congress. With regard to the relationship between lower respiratory tract infections and asthma, it emerges that is the number of respiratory episodes in the first years of life, but not the particular viral trigger, to be associated with later asthma development. Understanding which characteristics of individual patients are associated with an increased risk for asthma exacerbation is a critical step to implement strategies preventing these seasonal events. Recent data suggest the possibility that exhaled volatile organic compounds may qualify as biomarkers in detecting early signs of asthma. Adding information of exhaled volatile organic compounds and expression of inflammation genes to a clinical tool significantly improves asthma prediction in preschool wheezy children. Personal communication with children and adolescents is likely more important than the tools actually used for monitoring asthma. Systemic corticosteroids do not affect the long-term prognosis in children with first viral-induced wheezing episode and should be used cautiously during acute episodes. Finally, stress and a polymorphism upstream of a specific gene are both associated with reduced bronchodilator response in children with asthma.
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Kelly RS, Dahlin A, McGeachie MJ, Qiu W, Sordillo J, Wan ES, Wu AC, Lasky-Su J. Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic. Chest 2016; 151:262-277. [PMID: 27776981 DOI: 10.1016/j.chest.2016.10.008] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 09/26/2016] [Accepted: 10/07/2016] [Indexed: 12/11/2022] Open
Abstract
Asthma is a complex disease well-suited to metabolomic profiling, both for the development of novel biomarkers and for the improved understanding of pathophysiology. In this review, we summarize the 21 existing metabolomic studies of asthma in humans, all of which reported significant findings and concluded that individual metabolites and metabolomic profiles measured in exhaled breath condensate, urine, plasma, and serum could identify people with asthma and asthma phenotypes with high discriminatory ability. There was considerable consistency across the studies in terms of the reported biomarkers, regardless of biospecimen, profiling technology, and population age. In particular, acetate, adenosine, alanine, hippurate, succinate, threonine, and trans-aconitate, and pathways relating to hypoxia response, oxidative stress, immunity, inflammation, lipid metabolism and the tricarboxylic acid cycle were all identified as significant in at least two studies. There were also a number of nonreplicated results; however, the literature is not yet sufficiently developed to determine whether these represent spurious findings or reflect the substantial heterogeneity and limited statistical power in the studies and their methods to date. This review highlights the need for additional asthma metabolomic studies to explore these issues, and, further, the need for standardized methods in the way these studies are conducted. We conclude by discussing the potential of translation of these metabolomic findings into clinically useful biomarkers and the crucial role that integrated omics is likely to play in this endeavor.
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Affiliation(s)
- Rachel S Kelly
- Channing Division of Network Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA
| | - Amber Dahlin
- Channing Division of Network Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA
| | - Michael J McGeachie
- Channing Division of Network Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA
| | - Weiliang Qiu
- Channing Division of Network Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA
| | - Joanne Sordillo
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA
| | - Emily S Wan
- Channing Division of Network Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA; VA Boston Healthcare System, Department of Veterans Affairs, Boston, MA
| | - Ann Chen Wu
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA
| | - Jessica Lasky-Su
- Channing Division of Network Medicine, Brigham Women's Hospital and Harvard Medical School, Boston, MA.
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45
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van Mastrigt E, de Jongste JC, Pijnenburg MW. The analysis of volatile organic compounds in exhaled breath and biomarkers in exhaled breath condensate in children - clinical tools or scientific toys? Clin Exp Allergy 2016; 45:1170-88. [PMID: 25394891 DOI: 10.1111/cea.12454] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Current monitoring strategies for respiratory diseases are mainly based on clinical features, lung function and imaging. As airway inflammation is the hallmark of many respiratory diseases in childhood, noninvasive methods to assess the presence and severity of airway inflammation might be helpful in both diagnosing and monitoring paediatric respiratory diseases. At present, the measurement of fractional exhaled nitric oxide is the only noninvasive method available to assess eosinophilic airway inflammation in clinical practice. We aimed to evaluate whether the analysis of volatile organic compounds (VOCs) in exhaled breath (EB) and biomarkers in exhaled breath condensate (EBC) is helpful in diagnosing and monitoring respiratory diseases in children. An extensive literature search was conducted in Medline, Embase and PubMed on the analysis and applications of VOCs in EB and EBC in children. We retrieved 1165 papers, of which nine contained original data on VOCs in EB and 84 on biomarkers in EBC. These were included in this review. We give an overview of the clinical applications in childhood and summarize the methodological issues. Several VOCs in EB and biomarkers in EBC have the potential to distinguish patients from healthy controls and to monitor treatment responses. Lack of standardization of collection methods and analysis techniques hampers the introduction in clinical practice. The measurement of metabolomic profiles may have important advantages over detecting single markers. There is a lack of longitudinal studies and external validation to reveal whether EB and EBC analysis have added value in the diagnostic process and follow-up of children with respiratory diseases. In conclusion, the use of VOCs in EB and biomarkers in EBC as markers of inflammatory airway diseases in children is still a research tool and not validated for clinical use.
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Affiliation(s)
- E van Mastrigt
- Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - J C de Jongste
- Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - M W Pijnenburg
- Department of Paediatric Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
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46
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Bannier MAGE, van de Kant KDG, Jöbsis Q, Dompeling E. Biomarkers to predict asthma in wheezing preschool children. Clin Exp Allergy 2016; 45:1040-50. [PMID: 25409553 DOI: 10.1111/cea.12460] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Wheezing in preschool children is a very common symptom. An adequate prediction of asthma in these children is difficult and cannot be reliably assessed with conventional clinical tools. The study of potential predictive biomarkers in various media, ranging from invasive sampling (e.g. bronchoscopy) to non-invasive sampling (lung function testing and exhaled breath analysis), was comprehensively reviewed. The evolution in biomarker discovery has resulted in an 'omics' approach, in which hundreds of biomarkers in the field of genomics, proteomics, metabolomics, and 'breath-omics' can be simultaneously studied. First, results on gene expression and exhaled breath profiles in predicting an early asthma diagnosis are promising. However, many hurdles need to be overcome before clinical implementation is possible. To reliably predict asthma in a wheezing child, probably a holistic approach is needed, combining clinical information with blood sampling, lung function tests, and potentially exhaled breath analysis. The further development of predictive, non-invasive biomarkers may eventually improve an early asthma diagnosis in wheezing preschool children and assist clinicians in early treatment decision-making.
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Affiliation(s)
- M A G E Bannier
- Department of Paediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre, Maastricht, The Netherlands
| | - K D G van de Kant
- Department of Paediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Q Jöbsis
- Department of Paediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre, Maastricht, The Netherlands
| | - E Dompeling
- Department of Paediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre, Maastricht, The Netherlands
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Cavaleiro Rufo J, Madureira J, Oliveira Fernandes E, Moreira A. Volatile organic compounds in asthma diagnosis: a systematic review and meta-analysis. Allergy 2016; 71:175-88. [PMID: 26476125 DOI: 10.1111/all.12793] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2015] [Indexed: 01/01/2023]
Abstract
We aimed to assess the value and classification rate of exhaled volatile organic compounds (VOCs) in asthma diagnosis. A PRISMA-oriented systematic search for published studies regarding exhaled VOCs in asthma diagnosis was conducted based on predefined criteria. Studies presenting sensitivity and specificity values for the test were included in the meta-analysis. Pooled diagnosis odds ratios (DOR), area under the curve (AUC) and positive and negative likelihood ratios (LR) for exhaled VOC profiles were calculated; and publication bias, threshold effect and heterogeneity were estimated. Eighteen studies were selected for the qualitative analysis and six met the criteria for inclusion in the quantitative analysis. Mean (95% CI) pooled DOR, positive and negative LR were 49.3 (15.9-153.3), 5.86 (3.07-11.21) and 0.16 (0.10-0.26), respectively. The AUC value was 0.94. Only three of the 18 reviewed studies performed an external validation of the model using a different data set. The results from the revised studies suggest that exhaled VOCs are promising biomarkers for asthma diagnosis and that several compounds, mainly alkanes, may be significantly associated with asthma inflammation. However, there are still various constraints associated with standardization and externally validated studies are needed to introduce exhaled VOC profiling in a clinical scenario.
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Affiliation(s)
- J. Cavaleiro Rufo
- GEAC; INEGI - Institute of Science and Innovation in Mechanical Engineering and Industrial Management; Porto Portugal
- Faculty of Medicine of the University of Porto; Portugal & Centro Hospitalar São João E.P.E.; Porto Portugal
| | - J. Madureira
- GEAC; INEGI - Institute of Science and Innovation in Mechanical Engineering and Industrial Management; Porto Portugal
| | - E. Oliveira Fernandes
- GEAC; INEGI - Institute of Science and Innovation in Mechanical Engineering and Industrial Management; Porto Portugal
| | - A. Moreira
- Faculty of Medicine of the University of Porto; Portugal & Centro Hospitalar São João E.P.E.; Porto Portugal
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Caminati M, Durić-Filipović I, Arasi S, Peroni DG, Živković Z, Senna G. Respiratory allergies in childhood: Recent advances and future challenges. Pediatr Allergy Immunol 2015; 26:702-10. [PMID: 26582212 DOI: 10.1111/pai.12509] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/11/2015] [Indexed: 12/17/2022]
Abstract
The burden of allergic airway diseases still represents a major health problem in childhood. Despite many different options are currently available for the diagnostic work-up and management, the overall disease control in terms of impact on quality of life, morbidity and mortality, is not yet satisfactory. The extreme variability of individual risk factors and severity determinants may account for it. On the other side, the knowledge of the multifaceted allergy background could pave the way to primary prevention, early intervention and disease course modification. In fact, most of current research is focusing on the identification of biological and clinical predictive markers of allergy and asthma onset. This review aims at summarizing the latest achievements concerning the complex inter-relation between genetic predisposition and environmental factors, and their impact on prevention strategies and early identification of at risk subjects. An update on the diagnostic and monitoring tools as well as an insight into the newest treatments options is also provided.
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Affiliation(s)
- Marco Caminati
- Allergy Unit, Verona University and General Hospital, Verona, Italy
| | | | - Stefania Arasi
- Allergy Unit, Department of Pediatrics, University of Messina, Messina, Italy
| | - Diego G Peroni
- Department of Pediatrics, University of Ferrara, Ferrara, Italy.,International Inflammation (in-FLAME) Network of the World Universities Network, Ferrara, Italy
| | - Zorica Živković
- Children's Hospital for Lung Diseases and Tuberculosis, Medical Center 'Dr Dragisa Misovic', Belgrade, Serbia.,Faculty of Pharmacy, European University, Novi Sad, Serbia
| | - Gianenrico Senna
- Allergy Unit, Verona University and General Hospital, Verona, Italy
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Moschino L, Zanconato S, Bozzetto S, Baraldi E, Carraro S. Childhood asthma biomarkers: present knowledge and future steps. Paediatr Respir Rev 2015; 16:205-12. [PMID: 26100359 DOI: 10.1016/j.prrv.2015.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 05/06/2015] [Indexed: 11/28/2022]
Abstract
Asthma represents the most common chronic respiratory disease of childhood. Its current standard diagnosis relies on patient history of symptoms and confirmed expiratory airflow limitation. Nevertheless, the spectrum of asthma in clinical presentation is broad, and both symptoms and lung function may not always reflect the underlying airway inflammation, which can be determined by different pathogenetic mechanisms. For these reasons, the identification of objective biomarkers of asthma, which may guide diagnosis, phenotyping, management and treatment is of great clinical utility and might have a role in the development of personalized therapy. The availability of non-invasive methods to study and monitor disease inflammation is of relevance especially in childhood asthma. In this sense, a promising role might be played by the measurement of exhaled biomarkers, such as exhaled nitric oxide (FE(NO)) and molecules in exhaled breath condensate (EBC). Furthermore, recent studies have shown encouraging results with the application of the novel metabolomic approach to the study of exhaled biomarkers. In this paper the existing knowledge in the field of asthma biomarkers, with a special focus on exhaled biomarkers, will be highlighted.
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Affiliation(s)
- Laura Moschino
- Department of Women's and Children's Health, University of Padova, Padova Italy
| | - Stefania Zanconato
- Department of Women's and Children's Health, University of Padova, Padova Italy
| | - Sara Bozzetto
- Department of Women's and Children's Health, University of Padova, Padova Italy
| | - Eugenio Baraldi
- Department of Women's and Children's Health, University of Padova, Padova Italy
| | - Silvia Carraro
- Department of Women's and Children's Health, University of Padova, Padova Italy.
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50
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Klaassen EMM, van de Kant KDG, Jöbsis Q, van Schayck OCP, Smolinska A, Dallinga JW, van Schooten FJ, den Hartog GJM, de Jongste JC, Rijkers GT, Dompeling E. Exhaled biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age. Am J Respir Crit Care Med 2015; 191:201-7. [PMID: 25474185 DOI: 10.1164/rccm.201408-1537oc] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE A reliable asthma diagnosis is difficult in wheezing preschool children. OBJECTIVES To assess whether exhaled biomarkers, expression of inflammation genes, and early lung function measurements can improve a reliable asthma prediction in preschool wheezing children. METHODS Two hundred two preschool recurrent wheezers (aged 2-4 yr) were prospectively followed up until 6 years of age. At 6 years of age, a diagnosis (asthma or transient wheeze) was based on symptoms, lung function, and asthma medication use. The added predictive value (area under the receiver operating characteristic curve [AUC]) of biomarkers to clinical information (assessed with the Asthma Predictive Index [API]) assessed at preschool age in diagnosing asthma at 6 years of age was determined with a validation set. Biomarkers in exhaled breath condensate, exhaled volatile organic compounds (VOCs), gene expression, and airway resistance were measured. MEASUREMENTS AND MAIN RESULTS At 6 years of age, 198 children were diagnosed (76 with asthma, 122 with transient wheeze). Information on exhaled VOCs significantly improved asthma prediction (AUC, 89% [increase of 28%]; positive predictive value [PPV]/negative predictive value [NPV], 82/83%), which persisted in the validation set. Information on gene expression of toll-like receptor 4, catalase, and tumor necrosis factor-α significantly improved asthma prediction (AUC, 75% [increase of 17%]; PPV/NPV, 76/73%). This could not be confirmed after validation. Biomarkers in exhaled breath condensate and airway resistance (pre- and post- bronchodilator) did not improve an asthma prediction. The combined model with VOCs, gene expression, and API had an AUC of 95% (PPV/NPV, 90/89%). CONCLUSIONS Adding information on exhaled VOCs and possibly expression of inflammation genes to the API significantly improves an accurate asthma diagnosis in preschool children. Clinical trial registered with www.clinicaltrial.gov (NCT 00422747).
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