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CONTENTS Breath Test EDITORIAL BOARD Editor: Delane Shingadia Board Members Cristiana Nascimento-Carvalho (Bahia, Brazil) Ville Peltola (Turku, Finland) Emmanuel Roilides (Thessaloniki, Greece) Ira Shah (Mumbai, India) David Burgner (Melbourne, Australia) Kow-Tong Chen (Tainan,Taiwan) Luisa Galli (Florence, Italy) Steve Graham (Melbourne, Australia) George Syrogiannopoulos (Larissa, Greece) Tobias Tenenbaum (Mannhein, Germany) Marc Tebruegge (Southampton, UK) Marceline Tutu van Furth (Amsterdam, The Netherlands) The Pediatric Infectious Disease Journal • Volume XX, Number XX, XXX XXX www.pidj.com | 1 Accepted for publication August 10, 2021 From the *Pediatric Infectious Diseases and Immu- nology, Amalia Children’s Hospital; †Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences; ‡Radboud Center for Infectious Dis- eases; §Pediatric Pulmonology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen; and ¶Pediatric Infectious Diseases and Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. This work was supported by European Union’s Hori- zon 2020, project PERFORM, grant agreement No. 668303 and an ESPID fellowship grant to K.J.v.A. The authors have no conficts of interest to disclose. K.J.v.A. and R.J. contributed equally to the work. Address for correspondence: Koen J. van Aerde, MD, Consultant Pediatric Infectious Disease and Immunology, Amalia Children’s Hospital, Rad- boudumc, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. E-mail: koen.vana- erde@radboudumc.nl. ISSN: 0891-3668/21/XXXX-0000 DOI: 10.1097/INF.0000000000003310 Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. ESPID Reports and Reviews Breath Test Clinical Application of Breath Analysis in Lower Respiratory Tract Infection Diagnosis Koen J. van Aerde, MD,*†‡ Robin Jansen, BSc,† Peter J. Merkus, MD, PhD,§ and Michiel van der Flier, MD, PhD†¶ L ower respiratory tract infections (LRTIs) are responsible for >800,000 deaths per year in children younger than 5 years world- wide. 1 ). Methods to diagnose the etiology of LRTI are limited. Radiological imaging is traditionally used as a gold standard, but lacks precision. 2 Obtaining sputum specimens for microbial culture poses a challenge in the pediatric population; sputum induction can be unpleasant and bronchoalveolar lavage is an invasive method. Blood culture lacks sen- sitivity, and, in general, microbial culture can take several days to yield results. 2 Polymerase chain reaction detection of viral pathogens in upper respiratory tract samples does not dis- tinct symptomatic from asymptomatic viral infections. Metabolomic analysis of volatile organic compounds (VOCs) in exhaled breath is a promising noninvasive alternative to cur- rent methods to diagnose LRTI. 3 Its principle resembles the principle of breath tests used by the police to detect drunk drivers. In LRTI, diferent causative pathogens and host–patho- gen interactions can change the composition of the VOCs found in exhaled breath, which provides a potential target for diagnosis. 4 This review, aimed at the clinician, summarizes the diferent breath analysis techniques available, the diferent respiratory tract infections in which exhaled breath was studied and the challenges that come with breath research in children. BREATH ANALYSIS TECHNIQUES VOCs are organic molecules that are gaseous at room temperature, and can originate from host metabolism, pathogen metabolism and host–pathogen interactions. They can be detected using real-time tech- niques, in which the breath sample is directly introduced into the measuring instrument, or laboratory-based techniques, in which the exhaled breath is collected, stored and pre- processed. 4 The former are also known as online techniques, the latter as ofine tech- niques. A targeted approach is used to detect preselected VOCs, whereas an untargeted approach analyses unknown VOCs as well. MASS SPECTROMETRY TECHNIQUES Gas chromatography mass spectrom- etry (GC-MS) is considered the gold standard in breath research and uses preconcentrated breath samples for ofine analysis. GC-MS can be used for an untargeted approach, to provide chemical identifcation of the exhaled VOCs. 3,4 Other MS techniques, for example, selected ion fow tube MS, can per- form online untargeted or targeted analysis of VOCs, following chemical ionization. They have the potential to be developed into point- of-care tests. 4 ION MOBILITY SPECTROMETRY Ion mobility spectrometry, frequently coupled to a multicapillary gas chromatogra- phy column, allows online analysis of breath samples. In this technique, ions are separated in the gas phase by their mobility trough a controlled electrical feld. 4 ELECTRONIC NOSE Electronic nose (E-nose) devices, used for online breath analysis, apply a sensor- based technique which resembles mamma- lian olfaction. This technique cannot identify