ADVANCES IN ME/CFS RESEARCH AND CLINICAL CARE EDITED BY : Kenneth J. Friedman, Lucinda Bateman, Alison Bested and Zaher Nahle PUBLISHED IN : Frontiers in Pediatrics and Frontiers in Neurology Frontiers eBook Copyright Statement About Frontiers The copyright in the text of individual articles in this eBook is the Frontiers is more than just an open-access publisher of scholarly articles: it is a property of their respective authors or their respective institutions or pioneering approach to the world of academia, radically improving the way scholarly funders. The copyright in graphics research is managed. The grand vision of Frontiers is a world where all people have and images within each article may be subject to copyright of other an equal opportunity to seek, share and generate knowledge. Frontiers provides parties. In both cases this is subject immediate and permanent online open access to all its publications, but this alone to a license granted to Frontiers. is not enough to realize our grand goals. The compilation of articles constituting this eBook is the property of Frontiers. Frontiers Journal Series Each article within this eBook, and the eBook itself, are published under The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, the most recent version of the Creative Commons CC-BY licence. online journals, promising a paradigm shift from the current review, selection and The version current at the date of dissemination processes in academic publishing. All Frontiers journals are driven publication of this eBook is CC-BY 4.0. If the CC-BY licence is by researchers for researchers; therefore, they constitute a service to the scholarly updated, the licence granted by community. At the same time, the Frontiers Journal Series operates on a revolutionary Frontiers is automatically updated to the new version. invention, the tiered publishing system, initially addressing specific communities of When exercising any right under the scholars, and gradually climbing up to broader public understanding, thus serving CC-BY licence, Frontiers must be the interests of the lay society, too. attributed as the original publisher of the article or eBook, as applicable. Dedication to Quality Authors have the responsibility of ensuring that any graphics or other Each Frontiers article is a landmark of the highest quality, thanks to genuinely materials which are the property of collaborative interactions between authors and review editors, who include some others may be included in the CC-BY licence, but this should be of the world’s best academicians. Research must be certified by peers before entering checked before relying on the CC-BY licence to reproduce those a stream of knowledge that may eventually reach the public - and shape society; materials. Any copyright notices therefore, Frontiers only applies the most rigorous and unbiased reviews. relating to those materials must be complied with. Frontiers revolutionizes research publishing by freely delivering the most outstanding Copyright and source research, evaluated with no bias from both the academic and social point of view. acknowledgement notices may not By applying the most advanced information technologies, Frontiers is catapulting be removed and must be displayed in any copy, derivative work or scholarly publishing into a new generation. partial copy which includes the elements in question. All copyright, and all rights therein, What are Frontiers Research Topics? are protected by national and Frontiers Research Topics are very popular trademarks of the Frontiers Journals international copyright laws. The above represents a summary only. Series: they are collections of at least ten articles, all centered on a particular subject. For further information please read With their unique mix of varied contributions from Original Research to Review Frontiers’ Conditions for Website Use and Copyright Statement, and Articles, Frontiers Research Topics unify the most influential researchers, the latest the applicable CC-BY licence. key findings and historical advances in a hot research area! Find out more on how ISSN 1664-8714 to host your own Frontiers Research Topic or contribute to one as an author by ISBN 978-2-88963-206-0 DOI 10.3389/978-2-88963-206-0 contacting the Frontiers Editorial Office: [email protected] Frontiers in Pediatrics 1 November 2019 | ME/CFS Research and Clinical Care ADVANCES IN ME/CFS RESEARCH AND CLINICAL CARE Topic Editors: Kenneth J. Friedman, Retired, New Jersey Medical School, United States Lucinda Bateman, Bateman Horne Center, Salt Lake City, United States Alison Bested, Nova Southeastern University, United States Zaher Nahle, Arthritis National Research Foundation, United States About the Art The name of the painting is “Bring me along”. I stand in the dark, urging to be alive, please bring me along in your light. ME/CFS is a place of darkness. It is complete in both physical and mental state... Even light itself can make a person exhausted. Despite such darkness, patients reach out for help. Modified comments of the artist. About the Artist Solveig Evelyn Hopland is a Norwegian artist who paints in both romantic and surreal styles. Surreal painting allows her to express personal philosophies of what is important in life, and the big perspective of our existence. Image: Solveig E. Hopland. Frontiers in Pediatrics 2 November 2019 | ME/CFS Research and Clinical Care In 2015, the Institute of Medicine (USA) issued a report critical of the research effort and clinical care for ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) formerly known as Chronic Fatigue Syndrome (CFS) and Chronic Fatigue Immune Deficiency Syndrome (CFIDS). While worldwide investigation into the cause and nature of ME/CFS remains disproportionately small, and treatment remains symptomatic and controversial, modest research continues in all aspects of this disease: epidemiology, possible infectious origins and other triggers, possible involvement of genetics, metabolism, and microbiome, influence of co-morbid conditions, and more. Treatment of patients consists of providing symptomatic relief. Guidance in doing so is provided for the clinician. School-age children require not only treatment but, as revealed in a 25-year retrospective study, continued engagement with peers and social activity. This e-book explores the breadth and depth of current ME/CFS research and clinical care. Its impact for other chronic, complex illnesses should not be overlooked. Citation: Friedman, K. J., Bateman, L., Bested, A., Nahle, Z., eds. (2019). Advances In ME/CFS Research and Clinical Care. Lausanne: Frontiers Media SA. doi: 10.3389/978-2-88963-206-0 Frontiers in Pediatrics 3 November 2019 | ME/CFS Research and Clinical Care Table of Contents 07 Editorial: Advances in ME/CFS Research and Clinical Care Kenneth J. Friedman, Lucinda Bateman, Alison Bested and Zaher Nahle INTRODUCTION 10 Advances in ME/CFS: Past, Present, and Future Kenneth J. Friedman CAUSES AND TRIGGERS 18 Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Lily Chu, Ian J. Valencia, Donn W. Garvert and Jose G. Montoya 40 Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study Melanie Perez, Rajeev Jaundoo, Kelly Hilton, Ana Del Alamo, Kristina Gemayel, Nancy G. Klimas, Travis J. A. Craddock and Lubov Nathanson 47 Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Jonathan R. Kerr DISEASE CHARACTERIZATION - CASE DEFINITION 58 The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions Leonard A. Jason and Madison Sunnquist 67 The Importance of Accurate Diagnosis of ME/CFS in Children and Adolescents: A Commentary Keith James Geraghty and Charles Adeniji VALIDATING THE ME/CFS DIAGNOSIS 72 Hand Grip Strength as a Clinical Biomarker for ME/CFS and Disease Severity Luis Carlos Nacul, Kathleen Mudie, Caroline C. Kingdon, Taane G. Clark and Eliana Mattos Lacerda 82 Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Staci Stevens, Chris Snell, Jared Stevens, Betsy Keller and J. Mark VanNess 92 Low Sensitivity of Abbreviated Tilt Table Testing for Diagnosing Postural Tachycardia Syndrome in Adults With ME/CFS C. (Linda) M. C. van Campen, Peter C. Rowe and Frans C. Visser Frontiers in Pediatrics 4 November 2019 | ME/CFS Research and Clinical Care EPIDEMIOLOGY 98 Estimating Prevalence, Demographics, and Costs of ME/CFS Using Large Scale Medical Claims Data and Machine Learning Ashley R. Valdez, Elizabeth E. Hancock, Seyi Adebayo, David J. Kiernicki, Daniel Proskauer, John R. Attewell, Lucinda Bateman, Alfred DeMaria Jr., Charles W. Lapp, Peter C. Rowe and Charmian Proskauer LABORATORY RESEARCH 112 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Era of the Human Microbiome: Persistent Pathogens Drive Chronic Symptoms by Interfering With Host Metabolism, Gene Expression, and Immunity Amy Proal and Trevor Marshall 131 Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia 160 Corrigendum: Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods