Understanding the Behavioral and Medical Impact of Long COVID: An Empirical Guide to Assessment and Treatment of Post-Acute Sequelae of SARS CoV-2 Infection 9781032442235, 9781032442242, 9781003371090

Table of contents :
Cover
Half Title
Title Page
Copyright Page
Table of Contents
List of Contributors
Foreword
Chapter 1 Introduction: History, Diagnosis, and Classification
Chapter 2 Fatigue and Long-COVID
Chapter 3 Neurocognitive Disorders
Chapter 4 Brain and Nervous System
Chapter 5 Respiratory System
Chapter 6 Gastrointestinal Disorders
Chapter 7 Metabolic Disorders
Chapter 8 Long-Term Cardiovascular Disorders of COVID-19
Chapter 9 Autonomic Disorders
Chapter 10 Musculoskeletal Disorders
Chapter 11 Mental Health Disorders
Chapter 12 Alternative Treatment Approaches
Chapter 13 Menstrual Cycle and Female Reproductive Health Disturbance in the Covid Era
Chapter 14 Pediatric Issues
Chapter 15 Patient Perspectives on Long COVID Advocacy, Care, and Research
Afterword
Index

Citation preview

Understanding the Behavioral and Medical Impact of Long COVID

Understanding the Behavioral and Medical Impact of Long COVID serves to expand the research around the illness in order to enable health care researchers and practitioners to address the questions that are imperative to individuals suffering from this condition. Through its multi-faceted approach, the book puts forth a maturation of research and interventions that are theoretically sound, empirically valid, innovative, and creative in the Long COVID area. As a scholarly and scientific compilation of Long COVID symptoms and related disorders, this book offers unparalleled insight into the critical developments across medical areas treating this illness. It helps to fill the space that the pandemic created for knowledge of the condition, and contributes to the emerging emphasis on translational research blending the social sciences and biological fields. By putting forth the most optimal medical care practices in the treatment of complex Long COVID symptoms, this practical anthology will serve as a guide for practicing clinicians in assessment as well as treatment. It will also benefit researchers aiming to gain more understanding of Long COVID through its discussion of the critical developments in other medical areas treating the condition, and paves the way for the collaboration and future research needed to best support the global effort to mitigate the effects of this illness. This book will be essential reading for academics, practitioners, and researchers. It will appeal to individuals engaging with the fields of medicine, public policy, psychology, and for researchers looking to gain clarity about our current understanding of Long COVID. It will further be of interest to public/ government agencies, nonprofit organizations, and the general public wanting to gain more information about these ambiguous and evasive symptoms. Leonard A. Jason is currently a Professor of Psychology at DePaul University and the Director of the Center for Community Research. He has served on the editorial boards of ten psychological journals. He is part of the RECOVER consortium, and the chairperson of the Diagnostic Testing and Test Algorithms Subcommittee of the Commonalities with Other Post Viral Syndromes Task Force. He is also the Subject Matter Expert on ME/CFS for the Illinois RECOVER HUB program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the RECOVER Program, the NIH, or other funders. Dr. Charles Lapp, MD, is an Internal Medicine Specialist in Charlotte, NC, and has over 48 years of experience in the medical field with a particular emphasis in ME/CFS. He founded and is the Director of the HunterHopkins Center.

“If you want a thoughtful, broad-based look at the emerging biomedical condition of Long COVID, this is the volume to have! Edited by Leonard Jason, PhD and Charles Lapp, MD, each chapter covers a significant medical or behavioral aspect of Long COVID so you can easily focus in on your particular area of interest or concern. Well-described case studies illustrate key aspects of the illness. I strongly recommend this book!” Fred Friedberg, PhD, President, International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis “Understanding the Behavioral and Medical Impact of Long COVID is the first to take on the question of the long term consequences of SARS CoV-2 infection. If one needs to know what is known about this world-wide pandemic, this book is required reading.” Benjamin H. Natelson, MD, The Mount Sinai Hospital

Understanding the Behavioral and Medical Impact of Long COVID An Empirical Guide to Assessment and Treatment of Post-Acute Sequelae of SARS CoV-2 Infection Edited by Leonard A. Jason and Charles Lapp

Designed cover image: © Getty Images First published 2023 by Routledge 605 Third Avenue, New York, NY 10158 and by Routledge 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN Routledge is an imprint of the Taylor & Francis Group, an informa business © 2023 selection and editorial matter, Leonard A. Jason and Charles Lapp; individual chapters, the contributors The right of Leonard A. Jason and Charles Lapp to be identified as the author of the editorial material, and of the authors for their individual chapters, has been asserted in accordance with sections 77 and 78 of the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. ISBN: 9781032442235 (hbk) ISBN: 9781032442242 (pbk) ISBN: 9781003371090 (ebk) DOI: 10.4324/9781003371090 Typeset in Bembo by Deanta Global Publishing Services, Chennai, India

Contents

List of Contributors Foreword 1 Introduction: History, Diagnosis, and Classification

vii xii 1

LEONARD A. JASON, PH.D. AND CHARLES LAPP, MD

2 Fatigue and Long-COVID

18

KEITH GERAGHTY, PH.D. AND LEONARD A. JASON, PH.D.

3 Neurocognitive Disorders

35

ELIZABETA B. MUKAETOVA-LADINSKA, MD, PH.D., STELLA PADDICK, MD, PH.D., AND AKRAM A. HOSSEINI, MD, PH.D.

4 Brain and Nervous System

52

SUDHIR MEHTA, MD, FAMS, FRCP (LONDON & EDIN), FACP, FICP, GAURAV JAIN, MBBS DNB MNAMS, AND VARUN JAIN MD

5 Respiratory System

68

TANYA E. MELNIK, MD, MS, HEM DESAI, MBBS MPH, SARAH ZACH, BM, MS, CCC-SLP, AND STEPHANIE MISONO, MD MPH

6 Gastrointestinal Disorders

85

SONIA VILLAPOL, PHD

7 Metabolic Disorders

105

CHARLOTTE STEENBLOCK, PHD, NICOLE BECHMANN, PHD, WALDEMAR KANCZKOWSKI, PHD, NIKOLAOS PERAKAKIS, MD, AND STEFAN R. BORNSTEIN, MD



vi Contents 8 Long-Term Cardiovascular Disorders of COVID-19

122

MUHAMMAD HASSAN KHAN AND RICHARD C. BECKER

9 Autonomic Disorders

146

SŁAWOMIR KUJAWSKI, PHD, AGNIESZKA KUJAWSKA, MD, PHD, AND PAWEŁ ZALEWSKI, PHD

10 Musculoskeletal Disorders

163

HIDETOMI TERAI, MD, PHD, AND KOJI TAMAI, MD, PHD

11 Mental Health Disorders

179

YOCHAI RE’EM, MD, AND KARANBIR PADDA, MD

12 Alternative Treatment Approaches

197

TAE-HUN KIM, KMD, PHD

13 Menstrual Cycle and Female Reproductive Health Disturbance in the Covid Era

215

MICHELLE MAHER, MD, LAURA O’DOHERTY, MD, AND LISA OWENS, MD PHD

14 Pediatric Issues

232

CHRISTINE A. CAPONE, MD, MPH, ANNABELLE QUIZON, MD, ELIZABETH C. MITCHELL, MD, AND MARIA TERESA SANTIAGO, MD

15 Patient Perspectives on Long COVID Advocacy, Care, and Research

256

LISA MCCORKELL, MPP, HANNAH WEI, AND SIGNE REDFIELD, PHD

Afterword

277

LLEWELLYN KING

Index 279

Contributors

Benjamin H. Natelson, MD Professor of Neurology The Mount Sinai Hospital New York, New York, USA Leonard Jason, PhD Professor of Psychology Director, Center for Community Research Department of Psychology DePaul University Chicago, Illinois, USA Charles Lapp, MD Hunter-Hopkins Center Charlotte, North Carolina, USA Keith Geraghty, PhD Honorary Research Fellow Centre for Primary Care University of Manchester Manchester, UK Elizabeta B. Mukaetova-Ladinska, MD, PhD, FRCPsych Chair/Professor in Old Age Psychiatry Department of Psychology and Visual Sciences University of Leicester Leicester, UK Stella Paddick, MD, MRCPsych, PhD Associate Clinical Lecturer, Consultant in Old Age Psychiatry Gateshead Health NHS Foundation Trust and Newcastle University Newcastle, UK Akram A. Hosseini, MD, MRCP, PhD Consultant Neurologist Nottingham University Hospitals NHS Trust Nottingham, UK 

viii Contributors

Sudhir Mehta MD, FAMS, FRCP (London & Edin), FACP, FICP Senior Professor, Dept of Medicine SMS Medical College & Attached Group of Hospitals Jaipur, India Gaurav Jain, MBBS DNB MNAMS Assistant Professor Dept. Of Neurosurgery SMS Medical College Jaipur, India Varun Jain, MD Department of Neurology University of Florida Florida, USA Tanya E. Melnik, MD, MS Division of Geriatrics, Palliative and Primary Care University of Minnesota Minneapolis, Minnesota, USA Stephanie Misono, MD Associate Professor Division of Laryngology Department of Otolaryngology Head and Neck Surgery University of Minnesota Minneapolis, Minnesota, USA Hem Desai, MD Assistant Professor of Medicine Division of Pulmonary, Allergy, Critical Care and Sleep Medicine University of Minnesota Minneapolis, Minnesota, USA Sarah Zach, BM, MS, CCC-SLP Lions Voice Clinic Department of Otolaryngology University of Minnesota Minneapolis, Minnesota, USA Sonia Villapol, PhD Department of Neurosurgery Houston Methodist Research Institute Houston, Texas, USA

Contributors 

Charlotte Steenblock, PhD Department of Internal Medicine III University Hospital Carl Gustav Carus Technische Universität Dresden Dresden, Germany Nicole Bechmann, PhD Department of Internal Medicine III University Hospital Carl Gustav Carus Technische Universität Dresden Dresden, Germany Waldemar Kanczkowski, PhD Department of Internal Medicine III University Hospital Carl Gustav Carus Technische Universität Dresden Dresden, Germany Nikolaos Perakakis, MD Department of Internal Medicine III University Hospital Carl Gustav Carus Technische Universität Dresden Dresden, Germany Stefan R Bornstein, MD Department of Internal Medicine III University Hospital Carl Gustav Carus Technische Universität Dresden Dresden, Germany Richard C. Becker, MD Director, Physician-in-Chief Heart, Lung and Vascular Institute University of Cincinnati College of Medicine Cincinnati, Ohio, USA Sławomir Kujawski, PhD Department of Exercise Physiology and Functional Anatomy Ludwik Rydygier Collegium Medicum Bydgoszcz Nicolaus Copernicus University Toruń, Poland Agnieszka Kujawska, MD, PhD Department of Exercise Physiology and Functional Anatomy Ludwik Rydygier Collegium Medicum Bydgoszcz Nicolaus Copernicus University Toruń, Poland

ix

x Contributors

Paweł Zalewski, PhD Department of Exercise Physiology and Functional Anatomy Ludwik Rydygier Collegium Medicum Bydgoszcz Nicolaus Copernicus University Toruń, Poland and Department of Experimental and Clinical Physiology Laboratory of Centre for Preclinical Research Warsaw Medical University Warsaw, Poland Koji Tamai, MD Dept. of Orthopedic Surgery Osaka Metropolitan University Graduate School of Medicine Osaka, Japan Shinji Takahashi, MD Dept. of Orthopedic Surgery Osaka Metropolitan University Graduate School of Medicine Osaka, Japan Hidetomi Terai, MD Dept. of Orthopedic Surgery Osaka Metropolitan University Graduate School of Medicine Osaka, Japan Yochai Re'em, MD Department of Psychiatry Weill Cornell Medical College New York, USA Karanbir Padda, MD Department of Psychiatry New York University School of Medicine New York, USA Tae-Hun Kim, KMD, PhD Korean Medicine Clinical Trial Center College of Korean Medicine Kyung Hee University 23 Kyungheedae-ro Dongdaemun-gu, Seoul, South Korea Michelle Maher, MD Department of Endocrinology St James’s Hospital Dublin, Ireland

Contributors 

Laura O’Doherty, MD Department of Infectious Diseases St James’s Hospital Dublin, Ireland Lisa Owens, MD, PhD Department of Endocrinology Trinity College Dublin, Ireland Christine A. Capone, MD, MPH Pediatric Cardiology Cohen Children’s Medical Center New York, USA Lisa McCorkell, MPP Co-Founder | Patient-Led Research Collaborative Hannah Wei Co-Founder | Patient-Led Research Collaborative Signe Redfield, PhD Member | Patient-Led Research Collaborative Llewellyn King White House Chronicle

xi

Foreword

SARS CoV-2 has decimated the world. Worldwide, there have been over 626 million cases of patients with Covid. A recent Scottish study looking at symptoms at least 6 months after acute SARS-CoV-2 infection (Hastie et al., 2022) found that 6% showed no recovery and 42% only partial recovery; data were based on about 31,500 polymerase chain reaction positive patients compared to 63,000 never infected. This continued illness months after the acute infection has two names – Long COVID and post-acute sequelae of SARS CoV-2 infection (PASC). The Scottish data mean that we are in the midst of a second pandemic – Long COVID. Although not quick to respond, the United States National Institutes of Health have begun funding $1.2 billion across many academic centers to characterize Long COVID and develop possible treatments for it. The only good thing to emerge from this Long COVID pandemic is the realization that many of these patients also fulfill criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In fact, in our hands, of 41 patients whose continued symptoms over time lead to their being referred for cardiopulmonary exercise tests (Mancini et al., 2021), 47% fulfilled the 1994 case criteria (Fukuda et al., 1994) for the diagnosis of ME/CFS. This mini-epidemic of ME/CFS should sway health care providers away from the idea that this is a functional illness – a notion that has led to a significant amount of stigmatization of such patients (Green et al., 1999). One important area of study is to identify risk factors for who might be at increased risk of being continuously ill with Long COVID – female sex, prior history of depression, preexisting health conditions (Hastie et al., 2022), and circulating Epstein–Barr virus DNA and certain autoantibodies found during the acute infection (Su et al., 2022). This book edited by Drs. Leonard Jason and Charles Lapp, titled Understanding the Behavioral and Medical Impact of Long COVID, is the first to take on the question of the long-term consequences of SARS CoV-2 infection. As has to be the case, the book – looking across many organ systems – is limited to the current state of knowledge which is sparse for Long COVID. Thus, many of the chapters are forced to function about what is known about the acute 

Foreword  xiii

consequences of SARS CoV-2 infection. Nonetheless, if one needs to know what is known about this world-wide pandemic, this book is required reading. Benjamin H. Natelson, MD The Mount Sinai Hospital

References Fukuda, K., Straus, S.E., Hickie, I., et al. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121(12), 953–59. Green, J., Romei, J., Natelson, B.H. (1999). Stigma and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 5(2), 63–75. Hastie, C.E., Lowe, D.J., McAuley, A., et al. (2022). Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study. Nature Communications, 13(1), 5663. doi: 10.1038/s41467-022-33415-5 Mancini, D.M., Brunjes, D.L., Lala, A., et al. (2021). Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease. JACC Heart Fail 9(12), 927–37. doi: 10.1016/j.jchf.2021.10.002 Green, J., Romei, J., Natelson, B.H. (1999). Stigma and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 5(2), 63–75. Su, Y., Yuan, D., Chen, D.G., et al. (2022). Multiple early factors anticipate post-acute COVID-19 sequelae. Cell, 185(5), 881-95.e20. doi: 10.1016/j.cell.2022.01.014

1

Introduction History, Diagnosis, and Classification Leonard A. Jason, Ph.D. and Charles Lapp, MD

The study of COVID-19 (or coronavirus disease) has been fraught by a lack of coherence caused by a diverse presentation, “siloing” of research, and lack of a definition. This handbook addresses all these issues and more, for researchers and clinicians alike. COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), first described in late 2019, hence the term COVID-19. SARS-CoV-2 enters cells through ACE-2 receptors, which are present in the respiratory system, heart, brain, vascular endothelium and smooth muscle cells, gastrointestinal tract, kidney, spleen, pancreas, and liver (Howard-Jones et al., 2022). Mild to severe symptoms often occur 2–14 days after infection, and typically include fatigue, fever or chills, shortness of breath, and loss of taste or smell, as well as trouble breathing and persistent pain or pressure in the chest (Lechien et al., 2020; Li et al., 2020). As of September of 2022, there have been over 610 million confirmed cases and over 6.5 million deaths worldwide (Statista, 2022). According to the World Health Organization (2022, September 15), since November 2021, the variant Omicron is the dominant strain across the world (four other variants of concern are Alpha, Beta, Gamma, and Delta). While reports of lower severity for Omicron have emerged, nearly a third of the hospitalized Omicron patients have developed severe disease and 15% have died; its enhanced transmissibility continues to overwhelm health care systems. A proportion of persons infected with SARS-CoV-2 remain asymptomatic, and most people with COVID develop only mild (40%) or moderate (40%) disease, but approximately 15% develop severe disease that requires oxygen support. In addition to the health and economic consequences of this pandemic, many have experienced emotional difficulties, in part due to having to physically distance from friends, family, and coworkers. Effective vaccines have helped reduce the number and severity of cases of COVID-19. Based on our understanding of past epidemics such as the Spanish flu of 1918, SARS, Ebolavirus, and tick-borne encephalitis, a certain percentage of people will experience persisting symptoms or the development of new symptoms after viral or bacterial infections (Islam et al., 2020). There are some similar symptom profiles across post-acute infectious syndromes, including exertion intolerance and fatigue, impaired concentration or memory, trouble finding DOI: 10.4324/9781003371090-1

2 Introduction

words, malaise, and joint pain, but there are also infection-specific symptoms that suggest differences in pathogenesis such as eye problems (post-Ebola), irritable bowel syndrome (post-Giardia), anosmia and ageusia (post-COVID-19), and motor disturbances (post-polio and post-West Nile virus) (Choutka et al., 2022). The percentage of adults and youth with severe symptoms of these various infections is initially high, and then tends to decrease over time. As an example, Hickie et al. (2006) launched a prospective study following adult patients from the time of acute infection with Epstein–Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis). The occurrence of post-infective fatigue syndrome decreased over time: 35% at 6 weeks, 27% at 3 months, 12% at 6 months, and 9% at 12 months. Decreases have also occurred in pediatric samples, such as Katz et al.’s (2009) investigation of youth following infectious mononucleosis. Some SARS-CoV-2-infected individuals continue to have symptoms for weeks, months, or longer. Others have new symptoms weeks or months after their first symptoms of COVID-19 resolve (Centers for Disease Control, 2022a). Taquet et al. (2022) found that psychosis, dementia, seizures, and “brain fog” remain more common for as long as two years after COVID19 infection, whereas increased risks of depression and anxiety disappeared within two to three months. The persistence of symptoms at least four weeks post-SARS-CoV-2 infection, with no other clinical explanation, has been referred to as Long COVID (Health Library Ireland, 2022), or alternatively as post-acute sequelae of SARS-CoV-2 infection (PASC), long-haul COVID, post-acute COVID-19, long-term effects of COVID, and chronic COVID (Centers for Disease Control, 2022a). These symptoms have disabled many individuals, interfered with home and workplace functioning, strained social connections, and weakened the world’s economic infrastructure. Although the severity of the initial infection is predictive of higher risk of post-acute sequelae, frequently prolonged symptoms occur even after mild initial illness (Choutka et al., 2022). For example, Jim, whose illness started with flu-like symptoms, took off a few days from work and then returned. He was never hospitalized, but over the next month, new symptoms began to emerge. He lost his sense of taste, his hair began to fall out, and he continued to experience fatigue, shortness of breath, and difficulty concentrating. Three months later, he stopped working as symptoms in the cognitive areas made it difficult for him to perform in his high tech job, even though he could work from home. Jim had never had any serious illness before, and as a 40-year-old male, with a wife and 2 children, he seemed as if he had extremely good fortunes up to being infected with SARS-CoV-2. For the next eight months, he visited one health care specialist after another, and none could find any blood abnormalities or other reasons for the symptoms. Both Jim and his family often felt misunderstood by his health care professionals who continued to not provide any reasons for his persisting symptoms. Some health care workers have suggested that long COVID is largely due to psychosocial strain, depression and anxiety (Gaffney, 2022), or pandemic-related emotional and psychological

Introduction  3

distress (Devine, 2021), but findings from this volume suggest that these are simplistic and inaccurate explanations. In this volume, we hope to help those health care professionals who are treating individuals like Jim. We will review the health consequences of contracting COVID-19, as well as the consequences of experiencing persisting symptoms or the development of new symptoms. Choutka et al. (2022) suggest that those with PASC can be divided into two subsets, with the first group having lung or other organ damage as a result of acute respiratory distress syndrome or having lingering symptoms consistent with post-ICU syndrome. Symptoms may be caused by an inability to repair tissue damage imposed by the infection such as vascular damage and fibrosis in the lung that occur during acute respiratory infection. Other complications of COVID-19 infection can include lung scarring, blood clots, renal failure, neurological complications, and heart damage (Al-Aly et al., 2021; Parshley, 2020; Shi et al., 2020). The second subset have unexplained symptoms such as exertion intolerance, debilitating fatigue, and cognitive and sleep disorders, and they share many similarities with patients diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Choutka et al. (2022) review evidence that the original virus may establish a persistent infection or leave non-infectious remnants which can trigger innate immune activation and chronic stimulation of these lymphocytes can cause inflammatory conditions. Symptoms may be caused by autoimmune activation resulting either from the immune system trying to target the pathogen or from bystander autoimmune activation unrelated to the pathogen (Proal & VanElzakker, 2021). Estimates vary regarding how many of those previously infected with SARSCoV-2 have not fully recovered from COVID-19 (Komaroff & Bateman, 2021). Chen et al.’s (2022) meta-analysis of the worldwide prevalence of the Long COVID-19 condition was 37% at one month after diagnosis, 25% at two months, 32% at three months, and 49% at four months. If the global prevalence of PASC is estimated at 0.43%, based on the WHO estimation of worldwide COVID-19 infections, around 200 million people may be experiencing Long COVID symptoms (Chen et al., 2022). Initial reports described fatigue as the most reported Long COVID complication (Body Politic COVID-19, 2020; Lambert and Survivor Corps, 2020), followed by muscle or body aches, shortness of breath, and difficulty concentrating or focusing. Moreover, in a systematic review of 15 studies that reported on the long-term effects of Long COVID, involving 47,910 patients, Lopez-Leon et al. (2021) found the 5 most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Fernández-de-las-Peñas et al. (2021) concluded that most PASC symptoms fall into one of seven domains: neurocognitive, autonomic, gastrointestinal, respiratory, musculoskeletal, psychological, and “others.” The best estimate is that one in five have health conditions that might be related to their COVID illness (e.g., neurologic and mental conditions, kidney failure, musculoskeletal

4 Introduction

conditions, cardiovascular conditions, respiratory conditions, blood clots, and vascular issues) (Bull-Otterson et al., 2022). As will be indicated in this book, there is a need to examine co-morbidities and risks that compromise immune function including obesity, diabetes, old age, emphysema, cardiovascular disease, high blood pressure, smoking and vaping tobacco and marijuana products of any sort, and drug use. Predictors of post-acute symptoms remain largely unknown, although being a woman has repeatedly been found to be associated with a higher reported prevalence of symptoms (Choutka et al., 2022). Our book describes what is known about the impact of PASC in different areas of functioning, and how this knowledge can facilitate the application of appropriate assessment and treatment. We will illustrate the benefits that occur when multidisciplinary approaches help improve understanding of the complicated behavioral and biomedical systems of those affected by Long COVID. We hope to help clarify multiple questions, such as the question of what might be causing Long COVID at the molecular level (e.g., the persistence of SARSCoV-2 or its proteins or mRNA).

Classifying and Defining Long COVID The COVID pandemic has led to an urgent need for appropriate coding so that data can be captured for surveillance and health care claims. While patients with acute COVID are denoted by the International Classification for Diseases (ICD-10-CM) code U07.1, patients with Long COVID should receive a code specific to the “Post COVID-19 condition, unspecified” (U09.9) (Centers for Disease Control and Prevention, 2022b). For surveillance purposes, anyone with a “personal history of COVID-19 infection” should be designated Z86.16. At the present time, there is no one accepted definition of Long COVID, and we hope this book will provide a much needed way to find consensus on this issue. There are currently multiple definitions or frameworks proposed for studying Long COVID, varying by the types of symptoms, the timing of symptoms, and even the name to call the syndrome. If difficulties occur in arriving at a reliable case definition for any condition, there are serious consequences in estimating prevalence as well as finding biomarkers (Jason et al., 2021). The lack of consistency in the ways that Long COVID is being described, measured, and researched can create stigma and barriers to proper health care access (Siegelman, 2020). Researchers have proposed different frameworks for classifying PASC. As an example, Greenhalgh and colleagues (2020) have labeled symptoms existing for at least three weeks as “post-acute COVID-19.” They suggested that patients experiencing symptoms beyond 12 weeks should be classified as having “chronic COVID-19.” In contrast, Datta, Talwar, and Lee (2020) have proposed three stages, with the first stage being an acute infection of COVID19; some progress into a second stage called “post-acute hyperinflammation illness” which has an onset of two to five weeks after initial infection, and others

Introduction  5

move onto a stage called “late inflammatory and virological sequelae” that develops approximately four weeks after initial infection. There are multiple other duration classifications that have been proposed (Fernández-de-las-Peñas et al., 2021; Sudre et al., 2021). Many nations and federal authorities have also proposed ways to define PASC. For example, the World Health Organization (2021) developed a case definition for post-COVID-19 conditions. Their definition indicates that the syndrome occurs in individuals with a history of probable or confirmed SARSCoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others. A simpler system has been proposed by the Centers for Disease Control and Prevention in the US (Post-COVID conditions, 2022), who define postCOVID conditions as new, persistent, or evolving symptoms that are present four or more weeks after an initial SARS-CoV-2 infection. Finally, the UK National Institute for Health and Care Excellence (2020) have suggested this classification system: (1) ongoing symptomatic COVID-19 for people who still have symptoms between 4 and 12 weeks after the start of acute symptoms; and (2) post-COVID-19 syndrome for people who still have symptoms for more than 12 weeks after the start of acute symptoms.

A Five Axis Framework Elsewhere, Jason and Islam (2022) proposed a Five Axis system for PASC, and below we review these dimensions (Appendix A provides a copy of an instrument that captures this information, Jason & Dorri, 2023). Axis 1 would involve the COVID variants such as Alpha or Delta and their documentation (SARS-CoV-2 antibody test, polymerase chain reaction test). Of course, other characteristics of the person would be collected, but these COVID-19 factors would be prominent within the first Axis of a case definition for PASCID. Axis 2 involves the time elapsed since infection. Regarding the timing and length of symptoms, we believe it would be simpler to just indicate the amount of time that has elapsed since being infected or becoming sick, and anyone with persisting symptoms beyond four weeks would be classified as having long-haul COVID (Health Library Ireland, 2022). This would eliminate problems associated with individuals not being able to have a diagnosis and treatment at the critical early period in the illness. Axis 3 involves the type of medical collateral damage to different organs. There will be two types of PASC, those with clear organ damage versus those without it. Clear reasons for their persisting symptoms include post-ventilator syndromes or obvious damage or scarring in the lungs, heart, brain, or other

6 Introduction

organs (e.g., blood clots, renal failure, neurological complications, and heart damage). For those with unexplained symptoms, some will be diagnosed with ME/CFS. With Long COVID, particularly where the symptoms persist without easy-to-recognize organic damage, our health profession has experienced difficulties understanding the serious nature or legitimacy of their symptoms. Axis 4 involves functional impairment classified into three categories: mild, moderate, or severe. Jason and Islam (2022) used a seven-point Likert scale item to assess the severity of Long COVID patients’ impairment, ranging from “bedridden” (e.g., unable to move) to mild impairment. Participants who were bedbound or homebound were classified as “severely impaired.” Those who could work part-time and leave the house but did not have energy for other activities were classified as “moderately impaired.” Participants that responded as fully functional were classified as “mildly impaired.” This relatively simple rating scale can help differentiate patients into meaningful categories, and while all seem to improve over time, there are also important functional reductions between these groups. Finally, Axis 5 is the identified symptoms, and lists of symptoms are available such as COVID-19 surveys including Tran et al. (2022). Hughes et al. (2022) developed a symptom burden questionnaire for long COVID with promising psychometric methods – however, it is somewhat long with 17 independent scales tapping 131 items. Because there are so many possible symptoms, it might be useful to focus on the highest frequency representing 30–40 symptoms. We believe that there are advantages to classification systems that make a differentiation in the frequency and severity of symptoms. Many of the symptoms, such as fatigue, are common among individuals who have never had COVID. Therefore, simply that a person has a symptom is insufficient for designating at what threshold the symptom needs to exist for it to be considered a problem. A very infrequent symptom might not be a problem for the person even if it is rather serious when it occurs, and a very frequent symptom might also be less impactful when the severity of it is minimal. Therefore, including frequency and severity differentiations in symptoms makes it considerably easier to assess the impact of symptoms. In addition, the use of psychometrically sound questionnaires, so that it is more likely that the symptoms will be elicited similarly by different investigators, will reduce potential problems for interpreting and comparing the data (Jason et al., 2015; Sunnquist et al., 2019; Watson et al., 2014).

The Relationship between Long COVID and ME/CFS Some people infected with SARS-CoV-2 report symptoms experienced by patients with ME/CFS (Araja et al.,2021). For example, when Davis et al. (2021) studied an international sample of 3,761 patients with Long COVID, many had symptoms comparable to those with ME/CFS (i.e., fatigue, postexertional malaise, and cognitive dysfunction), and some have met criteria for ME/CFS (González-Hermosillo et al., 2021). When Jason et al. (2021)

Introduction  7

compared a sample of people with ME/CFS to those with Long COVID, both patient groups had high rates of ME/CFS symptoms including post-exertional malaise, cognitive impairment, and sleep disruptions. When contrasting the current COVID-19 symptoms with the ME/CFS group, the ME/CFS group was significantly more impaired on 39 symptoms, whereas the COVID-19 group was significantly more impaired on only 3 symptoms within the orthostatic domain (chest pain, shortness of breath, and irregular heartbeat). Bonilla et al. (2022) found 43% of the selected cohort fulfilled all the ME/CFS criteria, which is similar to the 46% reported by Mancini et al. (2021), 45% by Kedor et al. (2022), 47% by Haffke et al. (2022), and 49% by Jason and Islam (2022). Jason and Islam (2022) later found that those with Long COVID could be classified into three groups using a simple rating scale, and 74% of those in the severe group met a ME/CFS case definition (questionnaires to measure ME/ CFS and post-exertional malaise are included in Chapter 2). Several have postulated physiological similarities between Long COVID and ME/CFS (Araja et al., 2021; Komaroff & Bateman, 2021; Mackay, 2021). For example, Tate et al. (2022) believe that both ME/CFS and Long COVID arise by similar mechanisms involving neuroinflammation, although with the latter there is some unique signaling due to the pathology of the initial SARSCoV-2 infection. Many other similarities between ME/CFS and Long COVID have been found by investigators. For example, Campen et al. (2022) found early-onset orthostatic intolerance symptoms among those with PASC, which is also seen in patients with ME/CFS. Using an easy-to-perform orthostatic challenge, the 10-min NASA Lean Test, Vernon et al. (2022) found symptomatic, hemodynamic, and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control participants. Using more invasive cardiopulmonary challenges, Systrom (2022) has found a “preload failure” in patients with ME/CFS and those with Long Covid. This dysfunction refers to an inability to provide enough blood to the heart for it to fill properly, which reduces cardiac output and the amount of blood provided to the muscles during exercise. Natelson et al. (2022) have recently found that half of their patients with PASC have hypocapnia, low end tidal CO2 levels, which is indicative of hyperventilation. Research with ME/CFS has helped us understand that without including capnography, many manifestations of orthostatic intolerance would be missed in PASC. There are multiple advantages of learning about both Long COVID and ME/CFS. There is a substantive difference in precipitating events for these two illnesses, those with a single triggering event (Long COVID) versus those with a variety of triggering events (ME/CFS). There are certainly some differences in symptoms, as those with ME/CFS do not have the hair loss that occurs with Long COVID; however, if the majority of symptoms and biological abnormalities are comparable, then it is less likely that one trigger (SARS-CoV-2) is causing the debilitating long-term symptoms of Long COVID. If multiple triggers that occur in ME/CFS have comparable consequences as the one trigger

8 Introduction

in Long COVID, such a finding would have considerable policy and research implications. Most patients with Long COVID have been sick for just a few months or years. In contrast, the ME/CFS samples have generally been sick for longer periods of time. However, if it turns out that there are more similarities among these two large patient groups (Long COVID and ME/CFS), then based on what we know about ME/CFS, it may be possible to begin making predictions of what might occur over time for those with Long COVID. Such information could provide critical answers to questions now being discussed by scientists and government officials in the US and elsewhere. In addition, 60% of patients with ME/CFS report infectious illnesses before the onset of ME/CFS (Jason et al., 2021), and the most frequently reported infectious illness is mononucleosis, caused by the Epstein–Barr virus (EBV). According to Choutka et al. (2022), the initial SARS-CoV-2 infection might reactivate latent viruses like EBV in those with Long COVID, and this has been corroborated by Su et al. (2022). EBV is not the cause of Long COVID, but it could reactivate yielding some “positive” serologies, and this has considerable implications. A better understanding of EBV among these two important groups of patients would have considerable scientific advantages. From its earliest days, ME/CFS scientists have dealt with this issue of comorbidities, as many ME/CFS case definitions exclude a person from having ME/CFS if they had an explainable reason – i.e., a previously diagnosed medical condition whose resolution has not been documented beyond reasonable clinical doubt and whose continued activity may explain their chronic fatiguing illness. In other words, if cancer was causing their fatigue and other symptoms, they would have cancer fatigue but not ME/CFS. It will also be of importance for Long COVID researchers to gather sufficient information to determine if previous uncontrolled medical illnesses are present. We can learn from ME/CFS investigators how to collect adequate information to determine whether the patient’s persistent symptoms are due to an explained cause. At minimum, physicians should determine whether the patients have other active and untreated diseases processes that explain most of the major symptoms of post-exertional malaise, sleep disturbance, and cognitive impairment.

Conclusion The long-term persistence of symptoms is unknown, but findings from many studies reviewed above indicate that a certain percentage of those with Long COVID will have persisting symptoms. The fact that there are millions who have not recovered from this pandemic has created a thirst for knowledge among practitioners and researchers who are eager to learn about critical developments in a variety of medical areas for understanding and treating Long COVID. Our book is intended to guide the health care practitioners with new information on best medical care practice regarding how to treat patients with these complex Long COVID symptoms. We hope that readers will see the

Introduction  9

benefits of translational research profiled in this book that tactfully blends the medical, biological, and social sciences. There are many challenges to the research community as well as practicing clinicians in this emerging field of post-viral syndromes. For example, at the present time, there is not one accepted definition of Long COVID or PASC or the cause. Another example is how, after extensive diagnostic evaluations, Sneller et al. (2020) found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC. We also know little about different subtypes that exist. Using machine learning, Pfaff et al. (2022) found the best predictors of Long COVID were outpatient clinic utilization after acute COVID-19, patient age, dyspnea, and other diagnosis and medication features. They suggest that Long COVID might best be described as having subtypes, with each having its own symptoms, trajectories, and treatments. Finally, as Choutka et al. (2022) note, many epidemiological PASC studies have often centered on fatigue, which is widespread in the population, whereas better understanding post-exertional malaise might have unique advantages for better understanding Long COVID. To promote consistency in format, each chapter is comprised of two sections. The first is a critical review of the symptoms that are the focus of each chapter. There is a clear description of the general topic at the start of the chapter, anything we know about the prevalence of the types of symptoms in a particular area, and sometimes a case study or example of what they look like in a patient with Long COVID. Included are empirical findings underlining what is currently known and consideration of what we still need to learn. This is followed by a second section on how to apply the approach in real-world settings, including assessment strategies and possible treatments to help patients with Long COVID. We believe our book will enable health care researchers to answer questions that are important and beneficial to those suffering from Long COVID. In addition, we hope this book will stimulate academically based health care workers in various disciplines to contribute to the further maturation of research and intervention in ways that are theoretically sound, empirically valid, innovative, and creative.

References Al-Aly, Z., Xie, Y., & Bowe, B. (2021). High-dimensional characterization of post-acute sequelae of COVID-19. Nature, 594, 259–264. https://doi​.org​/10​.1038​/s41586​-021​ -03553-9 Araja, D., Berkis, U., Lunga, A., & Murovska, M. (2021). Shadow burden of undiagnosed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on society: Retrospective and prospective—in light of COVID-19. Journal of Clinical Medicine, 10(14), 3017. Body Politic COVID-19 Support Group. (2020). What does COVID-19 recovery look like? An analysis of the prolonged COVID-19 symptoms survey by patient-led research team. https://pat​ient​rese​arch​covid19​.com​/research​/report​-1/

10 Introduction Bonilla, H., Quach, T.C., Tiwari, A., Bonilla, A.E., Miglis, M., Yang, P.…. & Geng, L. (2022). Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic. Preprint available at: https://doi​.org​/10​.1101​/2022​.08​.03​ .22278363 Bull-Otterson, L., Baca, S., Saydah, S., et al. (2022). Post–COVID conditions among adult COVID-19 survivors aged 18–64 and ≥65 years — United States, March 2020– November 2021. Morbidity and Mortality Weekly Report, 71, 713–717. https://doi​.org​/10​ .15585​/mmwr​.mm7121e1external icon Campen, C.M.C.V., Rowe, P.C., & Visser, F.C. (2022). Orthostatic symptoms and reductions in cerebral blood flow in long-haul COVID-19 patients: Similarities with myalgic encephalomyelitis/chronic fatigue syndrome. Medicina, 58, 28. https://doi​.org​ /10​.3390/ Centers for Disease Control and Prevention (2022a). Long COVID. Available at: https:// www​.cdc​.gov​/coronavirus​/2019​-ncov​/long​-term​-effects​/index​.html Centers for Disease Control and Prevention (2022b). Annou​nceme​nt-ne​w-ICD​-code​ -for-​post-​covid​-cond​ition​. Available at: https://www​.cdc​.gov​/nchs​/data​/icd​/ Announcement​-New​-ICD- code-​​for​-P​​ost​-C​​ovid-​​Condi​​tion-​​April​​-2022​​​-fina​​l​.pdf​ Chen, C., Haupert, S.R., Zimmermann, L., Shi, X., Fritsche, L.G., & Mukherjee, B. (2022). Global prevalence of post COVID-19 condition or long COVID: A metaanalysis and systematic review. The Journal of Infectious Diseases, jiac136. https://doi​.org​ /10​.1093​/infdis​/jiac136 Choutka, J., Jansari, V., Hornig, M., & Iwasaki, A. (2022). Unexplained post-acute infection syndromes. Naure Medicine, 28, 911–923. https://doi​.org​/10​.1038​/s41591​ -022​-01810-6 Datta, S.D., Talwar, A., & Lee, J.T. (2020). A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection. Journal of the American Medical Association, 324(22), 2251–2252. Davis, H.E., Assaf, G.S., McCorkell, L., Wei, H., Low, R.J., Re'em, Y., Redfield, S., Austin, J.P., & Akrami, A., (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EclinicalMedicine, 38, 101019. https:// doi​.org​/10​.1016​/j​.eclinm​.2021​.101019 Devine, J. (2021). The dubious origins of Long Covid. Wall Street Journal, March 22. Available at: https://www​.wsj​.com​/articles​/the​-dubious​-origins​-of​-long​-covid​-11616452583x Fernández-de-las-Peñas, C., Palacios-Ceña, D., Gómez-Mayordomo, V., Cuadrado, M.L., Florencio, L.L. (2021). Defining post-COVID symptoms (Post-Acute COVID, long COVID, persistent post- COVID): An integrative classification. International Journal of Environmental Research and Public Health, 18(5), 2621. https://doi​.org​/10​.3390​/ ijerph18052621 Gaffney, A.W. (2022). The long COVID conundrum. American Journal of Medicine, 135(1), 5–6. https://doi​.org​/10​.1016​/j​.amjmed​.2021​.07​.037. Epub 2021 Aug 21. PMID: 34428463; PMCID: PMC8379817. González-Hermosillo, J.A., Martínez-López, J.P., Carrillo-Lampón, S.A., Ruiz-Ojeda, D., Herrera-Ramírez, S., Amezcua-Guerra, L.M., & Martínez-Alvarado, M.D.R. (2021). Post-acute COVID-19 symptoms, a potential link with myalgic encephalomyelitis/ chronic fatigue syndrome: A 6-month survey in a Mexican Cohort. Brain Science, 11, 760. https://doi​.org​/10​.3390​/brainsci11060760 Greenhalgh, T., Knight, M., A’Court, C., et al. (2020). Management of post-acute COVID19 in primary care. British Medical Journal, 370, m3026.

Introduction  11 Haffke, M., Freitag, H., Rudolf, G., et al. (2022). Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). Journal of Translational Medicine, 20(138). https://doi​.org​/10​.1186​ /s12967​-022​-03346​-2. Health Library Ireland (2022). What is the latest national and international evidence about the existence of long COVID or post-COVID and its persistence for COVID-19 survivors. Summary of Evidence: COVID-19. Available at: https://hselibrary​.ie​/wp​ -content​/uploads​/2020​/04​/COVID​-19​-Summary​-of​-Evidence​-Protocol​.pdf Hickie, I., Davenport, T., Wakefield, D., et al. (2006). Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: Prospective cohort study. British Medical Journal, 333, 575–80. doi:10.1136/bmj.38933.585764.AE Howard-Jones, A.R., Burgner, D.P., Crawford, N.W., et al. (2022). COVID-19 in children. II: Pathogenesis, disease spectrum and management. Journal of Paediatric Child Health, 58, 46–53. Hughes, S.E., Haroon, S., Subramanian, A., McMullan, C., Aiyegbusi, O.L., Turner, G.M. …, & Calvert, M.J. (2022). Development and validation of the symptom burden questionnaire for long covid (SBQ-LC): Rasch analysis. British Medical Journal, 377, e070230. https//doi​.org​/10​.1136​/bmj​-2022​​-070230 Islam, M.F., Cotler, J., & Jason, L.A. (2020). Post-viral fatigue and COVID-19: Lessons from past epidemics. Fatigue: Biomedicine, Health & Behavior, 8(2), 61–69. https://doi​.org​ /10​.1080​/21641846​.2020​.1778227 Jason, L.A., Kot, B., Sunnquist, M., Brown, A., Evans, M., Jantke, R., Williams, Y., Furst, J., & Vernon, S.D. (2015). Chronic fatigue syndrome and myalgic encephalomyelitis: Toward an empirical case definition. Health Psychology and Behavioral Medicine: An Open Access Journal, 3, 82–93. Jason, L.A., Cotler, J., Bhatia, S., & Sunnquist, M. (2021). Chronic illness: The case of chronic fatigue syndrome-myalgic encephalomyelitis. In D.F. Ragin & J.P. Keenan (Eds.), Handbook of Research Methods in Health Psychology (pp. 228–241). New York: Routledge. Jason, L.A., Islam, M., Conroy, K., Cotler, J., Torres, C., Johnson, M., & Mabie, B. (2021). COVID-19 symptoms over time: Comparing Long-Haulers to ME/CFS. Fatigue: Biomedicine, Health & Behavior, 9(2), 59–68. https://doi​.org​/10​.1080​/21641846​.2021​ .1922140 Jason, L.A., Yoo, S., & Bhatia, S. (2021). Patient perceptions of infectious illnesses preceding myalgic encephalomyelitis/chronic fatigue syndrome. Chronic Illness. Published online Sept. 20, 2021. https://doi​.org​/10​.1177​/17423953211043106 Jason, L.A., & Islam, M.F. (2022). A classification system for Post-Acute Sequelae of SARS CoV-2 Infection. Central Asian Journal of Medical Hypotheses and Ethics, 3(1), 38–51. https://cajmhe​.com​/index​.php​/journal​/article​/view​/146​/66 Jason, L.A., & Dorri, J. (2023). ME/CFS and post-exertional malaise among patients with Long-COVID. Neurology International, 15, 1–11. https://doi.org/10.3390/ neurolint15010001 Katz, B.Z., Shiraishi, Y., Mears, C.J., Binns, H.J., & Taylor, R. (2009). Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics, 124, 189–93. PMID: 19564299. Kedor, C., Freitag,H., Meyer-Arndt, L., Wittke, K., Hanitsch, L.G., Zoller, T.,… & Scheibenbogen, C. (2022). A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nature Community, 13(1), 5104. https://doi​.org​/10​ .1038​/s41467​-022​-32507-6

12 Introduction Komaroff, A.L., & Bateman, L. (2021). Will COVID-19 lead to myalgic encephalomyelitis/ chronic fatigue syndrome? Frontiers in Medicine, 7, 606824. https://doi​.org​/10​.3389​/ fmed​.2020​.606824 Lambert, N.J., Survivor Corps (2020). COVID-19 “long haulers” symptoms survey report. Available at: https://static1​.squarespace​.com​/static​/5e8​b5f6​3562​c031​c16e36a93​/t​ /5f459ef7798e8b60 37fa6​c57/1​59839​82151​20/20​​20​+Su​​rvivo​​r​+Cor​​ps​+CO​​VID19​+​ %27L​​ong​+H​​auler​​%27​+S​​ympto​​ms​+Su​​rvey+​​Repor​​t+​%28​​revis​​​ed​+Ju​​ly​+25​​.4​%29​​.pdf [Accessed 19 March 2021]. Lechien, J.R., Chiesa-Estomba, C.M., Place, S., et al. (2020). Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019. Journal of Internal Medicine, 288(3), 335–344. Li, R., Tian, J., Yang, F., et al. (2020). Clinical characteristics of 225 patients with COVID-19 in a tertiary hospital near Wuhan, China. Journal of Clinical Virology, 127, 104363. Lopez-Leon, S., Wegman-Ostrosky,T., Perelman, C., Sepulveda, R., Rebolledo, P.A., Cuapio, A., & Villapol, S. (2021). More than 50 long-term effects of COVID-19: A systematic review and meta-analysis. Scientific Reports, 11, 16144. https://doi​.org​/10​ .1038​/s41598- 021-95565-8 Mackay, A. (2021). A paradigm for post-Covid-19 fatigue syndrome analogous to ME/ CFS. Frontiers in Neurology, 12, 701419. https://doi​.org​/10​.3389​/fneur​.2021​.701419 Mancini, D.M., Brunjes, D.L., Lala, A., Trivieri, M.G., Contreras, J.P., & Natelson, B.H. (2021). Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease. JACC Heart Failure, 9(12), 927–37. Natelson, B.H., Lin, J.S., Blate, M., et al. (2022). Physiological assessment of orthostatic intolerance in chronic fatigue syndrome. Journal of Translational Medicine, 20(1), 95. https://doi​.org​/10​.1186​/s12967​-022​-03289-8 [published Online First: 2022/02/18]. National Institute for Health and Care Excellence (2020). COVID-19 rapid guideline: Managing the long-term effects of COVID-19. https://www​.nice. org​.uk​/guidance​/ n​g188 Parshley, P. (2020, May 8). The emerging long-term complications of COVID-19, explained. Available at: https://www​.vox​.com​/2020​/5​/8​/21251899​/coronavirus​-long​ -term​-effects- symptoms Pfaff, E.R., Girvin, A.T., Bennett, T.D., Bhatia, A., Brooks, I.M., Deer, R.R., Dekermanjian, J.P., Jolley, S.E., Kahn, M.G., Kostka, K., McMurry, J.A., Moffitt, R., Walden, A., Chute, C.G., Haendel, M.A., & The N3C Consortium (2022). Identifying who has long COVID in the USA: A machine learning approach using N3C data. Lancet, e532–e541. Post-COVID conditions (2022). Available at: https://www​.cdc​.gov​/coronavirus​/2019​ -ncov​/long​-term- effects/index​.ht​ml Proal, A.D., & VanElzakker, M.B. (2021). Long COVID or post-acute sequelae of COVID-19 (PASC): An overview of biological factors that may contribute to persistent symptoms. Frontiers in Microbiology, 12, 698169. Shi, S., Qin, M., Shen, B., et al. (2020). Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiology, 5(7), 802– 810. https://doi​.org​/10​.1001​/jamacardio​.2020​.0950 Siegelman, J.N. (2020). Reflections of a COVID-19 Long Hauler. Journal of the American Medical Association, 324(20), 2031–2032. https://doi​.org​/10​.1001​/jama​.2020​.22130 Sneller, M.C., Liang, C.J., Marques, A.R., Chung, J.Y., Shanbhag, S.M., Fontana, J.R., Raza, H., Okeke, O., Dewar, R.L., Higgins, B.P., Tolstenko, K., Kwan, R.W., Gittens, K.R., Seamon, C.A., McCormack, G., Shaw, J.S., Okpali, G.M., Law, M.,

Introduction  13 Trihemasava, K., Kennedy, B.D., Shi, V., Justement, J.S., Buckner, C.M., Blazkova, J., Moir, S., Chun, T.W., Lane, H.C. (2020). A longitudinal study of COVID-19 sequelae and immunity: Baseline findings. Annals of Internal Medicine, May 24. https://doi​.org​/10​ .7326​/M21​-4905. Statista (2022). Number of novel coronavirus (COVID-19) deaths worldwide as of 12, Sept. 2022, by country. https://www​.statista​.com​/statistics​/1093256​/novel​-coronavirus​ -2019ncov​-deaths- worldwide-by-country/ Su, Y., Yuan, D., Chen, D.G., et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell, 2022. https://doi/org/10.1016/j.cell.2022.01.014 Sudre, C.H., Murray, B., Varsavsky, T., et al. (2021). Attributes and predictors of longCOVID: Analysis of COVID cases and their symptoms collected by the COVID symptoms study app. Nat Med. Sunnquist, M., Lazarus, S., & Jason, L.A. (2019). The development of a short form of the DePaul symptom questionnaire. Rehabilitation Psychology, 64(4), 453–462. Systrom, D. (2022, July 28). Pathophysiology of exercise intolerance in ME/CFS & long COVID. Paper presented at the 15th Medical and Scientific Conference of the International Association of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Virtual. Taquet, M., Sillett, R., Zhu, L., Mendel, J., Camplisson, I., Dercon, Q., & Harrison, P.J. (2022). Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: An analysis of 2- year retrospective cohort studies including 1,284,437 patients. Lancet Psychiatry. https://doi​.org​/10​.1016​/S2215​-0366(22)00260-7 Tate, W., Walker, M., Sweetman, E., Helliwell, A., Peppercorn, K., Edgar, C., Blair, A. & Chatterjee, A. (2022). Molecular mechanisms of neuroinflammation in ME/CFS and long COVID to sustain disease and promote relapses. Frontiers in Neurology, 13, 877772. https://doi​.org​/10​.3389​/fneur​.2022​.877772 Tran, V.-T., Riveros, C., Clepier, B., Desvarieux, M., Collet, C., Vordanov, V., & Ravaud, P. (2022). Development and validation of the long coronavirus disease (COVID) symptom and impact tools: A set of patient-reported instruments constructed from patients' lived experience. Clinical Infectious Diseases, 74(2), 278–287. Vernon, S.D., Funk, S., Bateman, L., Stoddard, G.J., Hammer, S., Sullivan, K., Bell, J., Abbaszadeh, S., Lipkin, W.I., & Komaroff, A.L. (2022). Orthostatic challenge causes distinctive symptomatic, hemodynamic and cognitive responses in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Medicine, 9, 917019. https://doi​.org​/10​.3389​/fmed​.2022​.917019. PMID: 35847821; PMCID: PMC9285104. Watson, S., Ruskin, A., Simonis, V., Jason, L., Sunnquist, M., & Furst, J. (2014). Identifying defining aspects of chronic fatigue syndrome via unsupervised machine learning and feature selection. International Journal of Machine Learning and Computing, 4, 133–138. World Health Organization (2021). A clinical case definition of post COVID-19 condition by a Delphi consensus. World Health Organization, Inc. Available at: https:// www ​ . who ​ . int ​ / publications ​ / i ​ / item ​ / WHO ​ - 2019 ​ - nCoV ​ - Post ​ _ COVID ​ - 19​ _condition- Clinical_case_definition-2021.1 World Health Organization (2022, Sept. 15). Clinical management of COVID-19: Living guideline. Geneva: World Health Organization; 2022 (WHO/2019–nCoV/ Clinical/2022.2). https://creativecommons​.org​/licenses​/by​-nc​-sa​/3​.0​/igo

Research reported in this chapter was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS111105. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

14 Introduction

Appendix A DePaul Symptom Questionnaire-COVID

1. With which COVID variant were you infected? (Circle all that apply.) a. Alpha b. Beta c. Gamma d. Delta e. Omicron f. Other (please specify) _____________________________ g. Don’t know 2. How were you diagnosed with COVID? (Circle all that apply.) a. Positive PCR test b. Positive antigen result (rapid test) c. Positive antibody result (blood test) d. Positive result, but not sure which test e. Diagnosed by a doctor based on symptoms f. Self-diagnosed by symptoms 3. Have you been hospitalized for COVID? a. No b. Yes (how many days?) ______________ 4. While in the hospital, were you intubated for COVID? a. No b. Yes (how many days?) ______________ 5. Have you been vaccinated for COVID? (Circle one response.) a. No b. One shot, please specify what type of vaccine ______________ c. Two shots, please specify what types of vaccine _____________ 6. Have you had any COVID booster shots? (Circle one response.) a. No b. Yes, specify number and type _______________ 7. When did you begin having symptoms for COVID? (mm/dd/yyyy) __________ 8. Has there been documented damage done to one or more organ areas due to the COVID infection? (For example, respiratory, nervous system, metabolic, cardiovascular, stroke, gastrointestinal, arthritis, skin disorders, pulmonary embolism.) a. No b. Yes (please specify) _____​_____​_____​_____​_____​_____​_____​ _____​_____​___ 9. List any medical problems you had prior to being infected with COVID. _____​_____​_____​_____​_____​_____​_____​_____​_____​_____​_____​ _____​_____​_____​__

Introduction  15

10. Which statement best describes your fatigue/energy level over the last month? (Circle one response.) a. I am not able to work or do anything, and I am bedridden. b. I can walk around the house, but I cannot do light housework. c. I can do light housework, but I cannot work part-time. d. I can only work part-time at work or on some family responsibilities. e. I can work full-time, but I have no energy left for anything else. f. I can work full-time and finish some family responsibilities, but I have no energy left for anything else. g. I can do all work or family responsibilities without any problems with my energy. 11. Since the onset of your problems with fatigue/energy, have your symptoms caused a 50% or greater reduction in your activity level? (Circle one response.) a. No b. Yes c. Not having a problem with fatigue/energy For each symptom below, please circle one number for frequency and one number for severity. Please complete the chart from left to right. Frequency:

Severity:

Throughout the past month, how often have you had the symptoms listed below? For each symptom listed below, circle a number from: 0 = none of the time 1 = a little of the time 2 = about half the time 3 = most of the time 4 = all of the time

Throughout the past month, when a symptom below was present, how severe was it? For each symptom listed below, circle a number from: 0 = symptom not present 1 = mild 2 = moderate 3 = severe 4 = very severe

Symptom

Frequency:

Severity:

12. Fatigue/extreme tiredness 13. Cough 14. Loss of or change in smell and/or taste 15. Shortness of breath and/ or trouble breathing 16. Chest pain 17. Nose congestion 18. Loss of hair 19. Headache 20. Bone and/or joint pain

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

16 Introduction 21. Heavy legs and/or swelling of legs 22. Fever, chills, and/or sweating 23. Nerve problems (tremor, shaking, abnormal movements, numbness, tingling, burning, can't move part of body, new seizures) 24. Color changes in your skin such as red, white, or purple 25. Vision problems (blurry, light sensitivity, difficult reading or focusing, floaters, flashing light) 26. Memory loss 27. Problems with hearing (hearing loss, ringing in ears) 28. Anxiety 29. Depression 30. Gastrointestinal (belly) symptoms (pain, feeling full or vomiting after eating, nausea, diarrhea, constipation) 31. Weight loss 32. Sore throat 33. Palpitations, racing heart, arrhythmia, and/or skipped beats 34. Bladder problems (incontinence, trouble passing urine or emptying bladder) 35. Sleep problems 36. Changes in desire for, comfort with, or capacity for sex 37. Muscle aches 38. Ear pain 39. Dry eyes 40. Feeling faint, dizzy, and/ or difficulty thinking soon after standing up from a sitting or lying position

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

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0 1 2 3 4

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0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

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0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Introduction  17 41. Symptoms that get worse 0 1 2 3 4 0 1 2 3 4 after physical or mental activities (also known as post-exertional malaise) 42. Skin rash 0 1 2 3 4 0 1 2 3 4 43. Difficulty thinking and/ 0 1 2 3 4 0 1 2 3 4 or concentrating 44. Pins and needles feeling 0 1 2 3 4 0 1 2 3 4 45. Stress 0 1 2 3 4 0 1 2 3 4 46. Sore tongue, mouth, 0 1 2 3 4 0 1 2 3 4 and/or difficulty swallowing 47. Dry skin/peeling 0 1 2 3 4 0 1 2 3 4 48. Change in blood 0 1 2 3 4 0 1 2 3 4 pressure 49. Gynecological 0 1 2 3 4 0 1 2 3 4 symptoms (e.g., change in menstruation or menopause) 50. If you have or have had other symptoms, please list them below:_____________________ _____​_____​_____​_____​_____​_____​_____​_____​_____​_____​_____​_____​_____​ _____​_____​__ 51. Do you have what has been referred to as chronic fatigue syndrome, myalgic encephalomyelitis, or myalgic encephalomyelitis/chronic fatigue syndrome? (Circle one response below.) a. No b. Yes, already had this condition before I had COVID-19 c. Yes, I have this condition after I had COVID-19

2

Fatigue and Long-COVID Keith Geraghty, Ph.D. and Leonard A. Jason, Ph.D.

In the United Kingdom, the Office for National Statistics estimates 2 million people have symptoms of post-viral fatigue that continue for more than 4 weeks after SARS-CoV-2 infection (as of 4 June 2022). Due to LongCOVID symptoms, 409,000 individuals have reported that their ability to undertake their day-to-day activities has been “limited a lot” (Ayoubkhani, 2022). The same data set revealed that fatigue was the most common symptom reported by 56% for those infected by SARS-CoV-2, followed by shortness of breath (31%), loss of smell (22%), and muscle ache (21%). In addition, the most affected were those aged 35 to 69 years, females, people living in more deprived areas, those working in social care, health care, or teaching and education, and those with another activity-limiting health condition or disability. These types of findings have been replicated elsewhere, as indicated in this book, and studies across scientific areas have found that fatigue is the most common symptom reported by patients with Long-COVID. In response to the pandemic, multiple Long-COVID studies are ongoing, covering epidemiology, risk factors, biological markers, and pharmacological and behavioral treatment trials. These efforts will ultimately lead to better understanding of post-viral fatigue, as it is a symptom that is often associated with functional limitations related to difficulties for patients being able to return to work and to re-assume family responsibilities. There are multiple case definitions of Long-COVID, as reviewed in Chapter 1. One variation focusing on fatigue has been that of Sandler et al. (2021), who proposed the label “post-COVID fatigue.” They suggest this post-viral term should be applied when the fatigue is as follows: a dominant symptom; chronic; disabling to an extent that it interrupts all or a majority of normal activities (such as work/school attendance, social activities, etc.); persistent for 6 months or more (3 months in children/ adolescents); and emerged during confirmed acute COVID-19 (i.e., with a positive severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] test), without symptom free interval since onset. DOI: 10.4324/9781003371090-2

Fatigue and Long-COVID  19

Clearly, fatigue is one of the primary symptoms of Long-COVID, and this topic has for decades been investigated with patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this chapter, there is an extrapolation of knowledge and insights from what we already know about post-viral fatigue syndromes, particularly with regard to pathogenesis, prognosis, and treatment models over the past few decades. We will review how the medico-scientific community addressed post-viral fatigue syndrome. Lessons learned may help us offer Long-COVID clinicians and researchers clear signposts to assist in developing appropriate ways to treat patients experiencing severe fatigue. But first we review the prevalence of fatigue, which is one of the most common symptoms in the general population. Because acute fatigue is experienced by everyone at some point in time, often due to exertion or lifestyle activity, it is often more difficult to understand patients with more severe and frequent manifestations of this symptom.

The Prevalence of Fatigue and Post-Viral Fatigue Syndrome in Community Medicine Fatigue is one of the more common symptoms of patients in primary care. As an example, in a study from Ireland (Cullen et al., 2002), 89 general practitioners (family doctors), randomly selected from a directory, agreed to record the principal reasons for patient consultations; 25.6% of patients had complaints of fatigue. This study is representative of others, where fatigue is a common complaint, and the causes of this symptom range from the common cold to more serious health challenges like cancer. Fatigue is a widespread problem with about 25% of the population experiencing this symptom at any one time. The occurrence of general fatigue is quite different from chronic fatigue. In a community-based prevalence study (Jason et al. 1999), 4% to 5% of the general population experienced 6 or more months of chronic fatigue. That suggests that about 1 out of 20 people in the general population experiences chronic fatigue. One question that has arisen is whether these patients who have had chronic fatigue are either similar to or different from those with fatigue due to LongCOVID. We can begin to more fully understand this question by reviewing what is known about fatigue in the condition known as ME/CFS. Even before the pandemic, about 4 to 5% of the population experienced chronic fatigue, and about half the cases of chronic fatigue were due to medical (e.g. cancer) or psychiatric (e.g., depression) reasons. A key question involves how to determine how many of the remaining 2 to 2.5% have what is called ME/CFS. Early ME/CFS case definitions did not require key symptoms such as post-exertional malaise, and they are now considered broad case definitions. Such case definitions will include most of these 2 to 2.5% of individuals, but more recent case definitions that require cardinal symptoms such as post-exertional malaise would include only a small percentage of them (Wormgoor & Rodenburg, 2021). This is particularly important as over 40% of patients with Long-COVID are classified as meeting narrower ME/CFS case definitions,

20  Fatigue and Long-COVID

based on studies reviewed in Chapter 1. We will review below some of the challenges of measuring a somatic symptom such as fatigue, and the barriers that Long-COVID researchers might encounter in attempting to capture this construct.

The Challenge to Post-Viral Fatigue Syndrome Since the early 1900s, doctors have struggled to find ways of helping patients with fatigue due to a variety of causes. Some patients after a viral infection remain seriously functionally impaired and are often bedbound and housebound for years after the initial illness. Often, doctors are at a loss in terms of what to offer patients with fatigue, particularly when the majority of their vital signs are normal and no clear pathological complaints are detectable. This pattern is occurring for many Long-COVID patients, leaving doctors unable to explain their fatigue and other symptoms when standard medical testing often returns normal results, normal hormone levels, blood count, no raised white cells to indicate infection, no anemia, or clear abnormalities on magnetic resonance imaging. Later in this chapter, we will return to how health care professionals can respond to this challenge. Long-COVID is not the first time patients have had persisting fatigue following infection. Fatigue and other symptoms have been noted with infections such as post-Ebola, post-Giardia, and post-polio and post-West Nile virus (Islam et al., 2020). It is well known that viruses can cause fatigue and acute and chronic disease, e.g., the human immunodeficiency virus that causes acquired immunodeficiency syndrome. Meningitis and myelitis represent viral infections of the central nervous system. The number of cases of viral meningitis often exceeds that caused by bacterial pathogens. Lepow et al. (1962) outlined the role of enteroviruses, which account for the vast majority of all aseptic meningitis cases, as well as many focal infections of the spinal cord (Irani, 2008). All of these infections have documented links to patients encountering fatigue. Many of the common symptoms of post-viral fatigue syndrome – fatigue, headaches, pain, cognitive problems, anxiety, and muscle pain – may be explained by neurotropic viruses that cause diffuse low-grade inflammation and even meningitis. Common viral pathogens have been speculated to be the most likely culprits in post-viral fatigue syndrome pathogenesis, including Coxsackie A and B virus, human herpes viruses, specifically Epstein–Barr virus and Varicella-Zoster virus known as chickenpox, and Enteroviruses, and have all been implicated as possible triggers (Ariza, 2021; Chia & Chia, 2008). Interestingly, neurological inflammation is now evidenced in Long-COVID presentation (Visser et al., 2022), and is considered one of the leading causes of neuro-cognitive symptoms, and may also impact the neuro-muscular junction and thus may induce fatigue and muscle weakness.

Fatigue and Long-COVID  21

Medical Causes of Fatigue Recent emerging biomedical research into SARS-CoV-2 and LongCOVID, as evidenced in this book, has taken place at an accelerated rate given increased research funding and the urgent public health emergency. Findings point to mast cell activation syndrome, postural tachycardia syndrome, chronic inflammatory markers, and metabolic and endocrine changes in many (not all) Long-COVID patient cohorts. For instance, Iwasaki has identified a clear immune signature to distinguish Long-COVID patients from healthy controls – involving raised immune markers called cytokines and interleukins, combined with a clinical picture of low cortisol hormone levels and potential herpes virus reactivation (Klein et al., 2022). These raised immune markers can result in fatigue. Systrom has detected reduced pre-load to the heart in Long-COVID patients that may partially explain their fatigue and post-exertional malaise. This is a failure of the cardiovascular system, controlled by the autonomic nervous system, to orchestrate an increase in blood flow response to physical exertion (Singh et al., 2022). Add to this growing evidence of extensive neurological inflammation associated with Long-COVID (Visser et al., 2022), and we see that science has added a great deal of insight in a short time, to partially explain the existence of postacute fatigue and COVID-19 syndrome. What is also remarkable is the level of similarity between ME/CFS patient cohorts and Long-COVID patient cohorts in many of these studies.

Predictors of Vulnerability An important scientific question around Long-COVID is what triggers it, and we do at least know it occurs following the viral infection SARS-CoV-2. We also know that those who are older, and who have existing immunologic medical conditions, are more likely to get COVID and Long-COVID. But it is still unclear why one individual develops the condition, whilst another person infected with same pathogen does not. The best way to try to answer this type of question is by using prospective longitudinal studies involving people before they are infected with a virus causing post-viral fatigue. As an example, Jason et al. (2021) collected data on a cohort of 4,501 college students, of which 238 (5.3%) developed infectious mononucleosis. Baseline or pre-illness data was gathered for all the college students, some of whom recovered following infectious mononucleosis but others developed ME/CFS. Using this data set, Jason et al. (2022) found metabolic pre-illness pathways related to energy production, and their model correctly classified the narrow ME/CFS criteria group versus the recovered controls with a high degree of accuracy (97.2%), good sensitivity (94.4%), and excellent specificity (100.0%). These changes were consistent with the elevations in pre-illness pro-inflammatory cytokines for patients fated to develop ME/CFS 6 months after infectious mononucleosis. Prospective studies like these help us understand characteristics

22  Fatigue and Long-COVID

of patients that make them more likely to become infected and have persisting symptoms. This prospective study mentioned above involved infectious mononucleosis, which is caused by the Epstein–Barr virus, and there does appear to be a connection between Epstein–Barr virus (EBV) and Long-COVID. Su et al. (2022) has found evidence that SARS-CoV-2 infection might reactivate latent viruses like EBV in those with Long-COVID. Apostolou et al. (2022) also found 3–6 months after mild/asymptomatic SARS-CoV-2 infection, there was a strong reactivation of latent viruses (e.g. Epstein–Barr virus) in those who had ME/CFS as well as formerly healthy controls. The antibody responses were significantly stronger for the ME/CFS group.

Fatigue and Mental Health Issues There is a literature on the link between generalized fatigue and mental health illnesses. For example, in Canada, patients presenting with fatigue in the community tend to have slightly higher rates of psychiatric co-morbidities, depression and anxiety, and are more likely to report medically unexplained physical symptoms, greater perceived stress, more pathologic symptom attributions, and greater worries about having emotional problems than did other patients (Cathébras et al., 1992). A natural question is whether fatigue is just a consequence of depression or anxiety, or whether the mental health issues and fatigue are due to the aftermath of an event such as infection by a virus. In other words, as fatigue is common, and it is so often caused by psychological and lifestyle issues, it is important to differentiate those whose fatigue is due to these more psychogenic and lifestyle factors, versus those whose fatigue is due to more biologic factors, such as what occurs following a post-viral illness. With the use of validated and more precise questionnaires, it is possible to successfully differentiate those with solely psychiatric conditions like major depressive disorder from those dealing with a post-viral fatiguing illness (Hawk et al., 2006). Differentiating these fatiguing conditions has only occurred after years of research on specifying core symptoms, developing valid psychometric questionnaires, and specifying threshold values for what levels of symptoms are to be considered a burden to patients (Jason & Choi, 2008). Some of these critical scientific advances are discussed below, and they might be helpful to clinicians and scientists trying to better understand the fatigue felt by patients with Long-COVID.

Occurrence versus Frequency/Severity Measures For many years, research in the ME/CFS field only assessed whether or not fatigue was present, but in the 1990s, it was apparent that low levels of somatic symptoms like fatigue in patients with ME/CFS were so very common that occurrence measures were not able to differentiate patients with ME/CFS from controls or other groups (Jason et al., 1999). The field then moved to

Fatigue and Long-COVID  23

assess the frequency of symptoms rather than just the occurrence of symptoms in patients with post-infectious fatigue. Healthy individuals do experience fatigue, but those with ME/CFS experience it much more frequently, so using frequency measures was initially thought to be a useful way to differentiate patients with fatigue from those who are healthy. However, researchers encountered another conceptual problem with frequency measures when comparing post-viral fatigue syndromes versus psychiatric conditions. For example, patients with major depressive disorder had a similar high frequency of fatigue as patients with ME/CFS. In other words, one of the most prevalent mental health disorders (e.g., major depressive disorder) could not be differentiated from ME/CFS using just measures of frequency. However, when measures of severity were introduced, those with ME/CFS could be successfully differentiated from patients with major depressive disorder (King & Jason, 2005). Both frequency and severity are important to assess somatic symptoms. An infrequent symptom might not be a problem for the person even if it is rather serious when it occurs (such as having a migraine once every 2 months), and a very frequent symptom might also be less impactful when the severity of it is minimal (having minor pain in one part of the body). It is only by considering both frequency and severity that we can fully understand whether a particular symptom, such as fatigue, is a burden and needs to be counted as a symptom of Long-COVID. Overall, by assessing both the frequency and severity of symptoms, it was possible to make the important diagnostic differentiation between ME/CFS and psychiatric conditions. Unfortunately, most Long-COVID questionnaires continue to primarily assess fatigue and other somatic symptoms using occurrence measures, rather than measures of frequency and severity. Patients are asked in many of the current interview schedules assessing Long-COVID whether a symptom has occurred, but as many somatic symptoms are widespread in community and clinic samples, these efforts do not provide a useful threshold for deciding whether a problem like fatigue is severe enough to be a problem or burden to the participants. There is also a need to determine what symptom frequency and severity scores make the best threshold for discriminating whether a person has an illness versus those that do not. For example, if one adopts the criterion of a symptom being counted if the frequency is a “little of the time” and severity as “mild,” too many symptoms would be counted as a burden. However, if the frequency was set at “half the time” and severity as “moderate,” then the identified symptom would be more reasonable to count as a burden to the individual. There are scientific ways of deciding on thresholds, such as when Watson et al. (2014) dynamically adjusted the threshold for each symptom based on observed frequency and severity scores with a ME/CFS sample and controls. This was achieved through a k-means clustering approach. Using this system, the questions with the highest sensitivity and specificity were identified. Fortunately, the results of using the framework that involved a frequency of “half the time” and severity of “moderate” were rather close to using this

24  Fatigue and Long-COVID

unsupervised learning strategy (Jason et al., 2015), and these qualities were integrated into the DePaul Symptom Questionnaire (the short form of the questionnaire is in Appendix A, and Appendix B has an instrument to measure post-exertional malaise). In addition, the majority of current COVID surveys of symptoms have unclear validity and reliability. As an example, rather than using a psychometrically sound instrument to assess ME/CFS symptoms to determine if the person might have ME/CFS, most Long-COVID questionnaires merely ask about whether the person has ME/CFS. However, in adult and pediatric community-based epidemiologic studies, from 90% to 95% of patients with ME/ CFS do not know they have ME/CFS (Jason et al., 1999; Jason et al., 2020). In addition, many individuals who think they have ME/CFS do not meet case definitions. Due to participants not knowing the symptoms of ME/CFS, it is not sufficient to just ask patients whether they have ME/CFS, as most have no idea of what symptoms are in the established ME/CFS case definitions. In addition, asking the participants whether they had been diagnosed with ME/ CFS has problems in that many health care practitioners have difficulties making accurate diagnoses as they are not familiar with established ME/CFS case definitions. To determine if patients might have ME/CFS and chronic fatigue, as well as Long-COVID symptoms, psychometrically sound questionnaires should be used.

The Cause-and-Effect Debate It is instructive to review the history of ME/CFS, in terms of the changing models in which scientists and clinicians have assessed and treated patients, many of whom have overlapping symptoms with Long-COVID. In the 1980s and 1990s, researchers found that most patients with ME/CFS reported that their illness started after a viral or other infection. Not only did most patients with ME/CFS report an infectious cause, they did not feel that a psychological illness played a significant part in their ongoing fatigue and health problems (Deale & Wessely, 2001). However, some researchers felt this was not correct, as they believed psychiatric and lifestyle conditions were maintaining their illness (Wessely, 1997). For example, McEvedy and Beard’s theory in the 1970s defined cluster outbreaks of ME/CFS as cases of mass hysteria. David et al. (1988) maintained that post-viral fatigue syndromes should be viewed through the lens of a psychogenic model (Wessely, 1997). This model suggested that while a virus had caused the initial fatiguing symptoms, continued disability was being maintained by a phobic fear of engaging in activity, and the subsequent lack of exercise then led to more fatiguing problems and deconditioning. Some have used terms for medically unexplained symptoms that include somatoform disorders (Picariello et al., 2015), and more contemporary terms include bodily distress disorder or bodily distress syndrome. Several have proposed theories whereby psychosomatic disorders and neurosis lay at its core. The roots of this psychogenic perspective go back to the epidemic that occurred

Fatigue and Long-COVID  25

at the Royal Free Hospital in 1955, which Thomas (National Achieves UK, 2022) characterized as mass hysteria and the patient needs to be persuaded to accept the underlying depression as an explanation for the symptoms. In addition, it was felt that if medical investigations fail to find evidence to support patients’ claims about their level of ME/CFS fatiguing symptoms, then their disability must be “a perception problem,” most likely part of a psychocognitive disorder, and not a biological problem (Wessely et al., 1998). A plethora of other reasons have been tagged onto this central concept over the years, suggesting that patients seek to avail of sick-role status (Parson’s classic sick role) (Becker, 1952), or that doctors give way to overly assertive patients and label them with ME/CFS to appease them (Stanley et al., 2002), and other social and cultural factors, such as the existence of state disability benefits, medical fashions, and fads (Wessely, 1997). Given this psychogenic model, those treating ME/CFS felt that patients’ beliefs and behaviors should be managed with cognitive behavior therapy and graded exercise therapy (Butler et al., 1991; Sharpe, 1995; Wessely et al., 1989). With graded exercise, patients were instructed to increase time exercising over time despite the occurrence of symptoms. The same psychogenic model has now been promoted for Long-COVID management. For example, David (2021) has proposed somatization as the causative “singular mechanism” in Long-COVID. David (2021) believes that health care providers should minimize trying to find the cause of patients’ symptoms if routine medical testing fails offer quick returns, and doctors should consider alternative psychological causes, like somatization disorder, anxiety, and depression. Over the last decade, this psychogenic model has been seriously questioned. As an example, in 2021, the National Institute for Health and Care Excellence removed graded exercise therapy as a recommended treatment for ME/CFS and downgraded cognitive behavior therapy to the status of a support therapy (Torjesen, 2022). There is lack of evidence for the view that Long-COVID and ME/CFS are somatization disorders. Some patients with Long-COVID might overly focus on physical symptoms, such as fatigue, pain, weakness, or shortness of breath, as shortness of breath is highly distressing, inducing anxiety or panic. If such symptoms persist, patients would obviously focus on it, and this may be detected as “symptom-focusing.” Chronic fatigue, pain, and sleep disturbance can quickly impact quality of life and become physically and emotionally debilitating. Patients experiencing unexplained symptoms may also experience anxiety and depression. However, a clear distinction needs to be drawn between “expected complaints” that result from Long-COVID and “somatization disorder” or “hypochondriasis disorder,” which are discrete psychiatric conditions. It is clear that illnesses like Long-COVID and ME/CFS challenge doctors’ knowledge and skills, especially when the symptoms like fatigue do not conform to recognizable patterns (Chew-Graham et al., 2017). However, some look for psychological reasons instead of medically unexplained symptoms that are difficult to diagnose or treat (Scott et al., 2022). Evidence in this volume suggests that a body of research supports a biologic explanation of those with

26  Fatigue and Long-COVID

post-viral fatigue symptoms and Long-COVID, but there remain some supporters of this earlier ME/CFS psychogenic paradigm (David, 2021).

A Way Forward in Long-COVID Today, the COVID treatment landscape recognizes pathophysiological elements within fatigue such as chronic low-grade inflammation, vascular coagulation, tissue hypo-oxygenation, and possible neurotransmitter dysregulation, as indicated in many chapters in this book. There is a role for mental health professionals, as reflected in this quote: “In our experience, psychologists play a key role in the management of long COVID by providing education, validation, reassurance, support, and direction” (Rivas-Vazquez et al., 2022, p. 27). Increasingly, academics in psychology and medicine are cognizant of the difficult issues at play in the patient management protocol development of fatigue and other symptoms. For example, in an article in Lancet Psychiatry in the early months of the pandemic, Siddaway wrote, Researchers investigating individual, societal, media, and mental health service responses to COVID-19 must avoid assuming psychological problems in people who are experiencing COVID-19-related distress. (Siddaway, 2020) Siddaway goes on to say that caution should be taken against assuming that psychological responses to the pandemic are in some way different to those for other life stressors, adversities, and traumas. Essentially, certain psychological responses are exactly those we should expect in such a scenario, including for people now living with Long-COVID and their families and carers. So, new and worrying bodily symptoms are to be expected to a degree; job loss or social isolation should cause a certain level of depressed mood. Long-COVID might also contribute towards exacerbating mental health difficulties in some individuals who were already experiencing psychological problems, or contribute towards the onset of new problems in some individuals who are vulnerable (Siddaway, 2020). Lockdowns in the United Kingdom and elsewhere prevented people from easily accessing the types of social support that might buffer them from psychological illness, especially those most susceptible.

Discussion Today, health care professionals are less likely to attribute a psychogenic notion to Long-COVID, even though some (David, 2021) continue to propose somatization as an explanation for Long-COVID. A psychogenic explanation is hardly likely to be the appropriate roadmap to treat this post-viral disease. More likely, health practitioners will attempt to offer their patients new treatments as research findings emerge that add to what we know about ME/CFS, post-viral fatigue syndrome, and Long-COVID.

Fatigue and Long-COVID  27

Future models of Long-COVID care should be cognizant of the abundance of bioscience research that has revealed biomedical abnormalities that can contribute to fatigue, principally neuro-immune, associated with post-viral fatigue syndromes and ME/CFS (Green et al., 2015; Holgate et al., 2011), and rapidly advancing science around genomics, proteomics and metabolomics (Nagy-Szakal et al., 2018), and disruption to cellular biology (Nagy-Szakal et al., 2018) only adds to this knowledge-base. It may be a tall order for any time-pressed clinician to keep up-to-date with developments in this field, but doctors should at least be aware of the history, controversy, and most recent scientific developments. Seeking tests to explain new or debilitating symptoms such as fatigue is a logical response for Long-COVID patients. Tests may, or may not, reveal underlying pathology. Fatigue is rather difficult to test for; however, findings from studies by Iwasaki and colleagues (Klein et al., 2022) and Systrom and colleagues (Singh et al., 2022) reveal a neuro-immunological pattern of post-viral illness in Long-COVID. Viral infections have also been linked with neurological inflammatory processes that heighten bodily sensations via a process of “central sensitisation” and dysregulation of CNS signaling (Meeus & Nijs, 2007). When doctors encounter worried patients with fatigue and heightened bodily sensations, they may be inclined to consider a diagnosis of health anxiety or somatization disorder, or refer to psychiatry or psychology departments; however, doctors should carefully consider the possible origins of such behavior in Long-COVID patients. Loss of functional abilities and social dislocation, such as being unable to return to work due to lingering symptoms of fatigue or pain, is also a rational reason for concern and health anxiety. It is important to avoid a psychogenic explanation of Long-COVID, and we should not make the mistake of offering psychological treatment as a substitute for good medical care. Few patients with either Long-COVID or ME/CFS may be offered advanced immunological tests, tilt-table tests for postural tachycardia syndrome, allergy testing for mast cell activation syndrome, or bioenergetic testing for post-exertional malaise. These conditions should be considered in the clinical assessment of Long-COVID patients and are amenable to treatment. Chronic illness impacts physical and mental health, a body-mind connection. A study in Lancet Psychiatry provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection (Taquet et al., 2021). Management of Long-COVID should include a focus on mental health and psychological wellbeing. A lack of pathological evidence in a community physician’s office to explain presenting fatigue and other symptoms should not be viewed as evidence for possible psychosomatic disorder, hypochondriasis, conversion disorder, or somatization disorder. It is important for doctors to try to understand the origins of physical and psychological disturbances in Long-COVID and reconcile the biological, psychological, and social factors. Clinicians working with Long-COVID patients may be best served by adopting a pragmatic patient-centered approach. Clinical practice in LongCOVID should be evidence-based and focused on addressing patients’ needs, rather than a prescriptive one-size-fits-all approach (Goldberg et al., 2022).

28  Fatigue and Long-COVID

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Fatigue and Long-COVID  29 Geraghty, K. J., & Esmail, A. (2016). Chronic fatigue syndrome: Is the biopsychosocial model responsible for patient dissatisfaction and harm? British Journal of General Practice, 66(649), 437–438. https://doi​.org​/10​.3399​/bjgp16x686473 Ghaemi, S. N. (2010). The rise and fall of the biopsychosocial model: Reconciling art and science in psychiatry. JHU Press. https://doi​.org​/10​.1192​/bjp​.bp​.109​.063859 Goldberg, N.C., Poirier, S., Kanas, A., McCorkell, L., McGinn, C.A., Re’em, Y., Kuehnel, K., Muirhead, N., Ruschioni, T., Taylor-Brown, S., Jason, L.A. (2022, Oct. 10). A new clinical challenge: Supporting patients coping with the long-term effects of COVID-19. Fatigue: Biomedicine, Health & Behavior. Advance online publication https://doi​.org​/10​ .1080​/21641846​.2022​.2128576 Green, C. R., Cowan, P., Elk, R., O'Neil, K. M., & Rasmussen, A. L. (2015). National institutes of health pathways to prevention workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine, 162(12), 860. https://doi​.org​/10​.7326​/m15​-0338 Hawk, C., Jason, L.A., & Torres-Harding, S. (2006). Differential diagnosis of chronic fatigue syndrome and major depressive disorder. International Journal of Behavioral Medicine, 13, 244–251. Holgate, S. T., Komaroff, A. L., Mangan, D., & Wessely, S. (2011). Chronic fatigue syndrome: Understanding a complex illness. Nature Reviews Neuroscience, 12(9), 539–544. https://doi​.org​/10​.1038​/nrn3087 Hunt, J., Blease, C., & Geraghty, K. J. (2022). Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Journal of Health Psychology, 13591053221084494. https:// doi​.org​/10​.1177​/13591053221084494 Irani, D. N. (2008). Aseptic meningitis and viral myelitis. Neurologic Clinics, 26(3), 635-viii. https://doi​.org​/10​.1016​/j​.ncl​.2008​.03​.003 Islam, M.F., Cotler, J., & Jason, L.A. (2020). Post-viral fatigue and COVID-19: Lessons from past epidemics. Fatigue: Biomedicine, Health & Behavior, 8(2), 61–69. https://doi​.org​ /10​.1080​/21641846​.2020​.1778227 Jamal, G. A., & Hansen, S. (1985). Electrophysiological studies in the post-viral fatigue syndrome. Journal of Neurology, Neurosurgery & Psychiatry, 48(7), 691–694. https://doi​ .org​/10​.1136​/jnnp​.48​.7​.691 Jason, L.A., & Choi, M. (2008). Dimensions and assessment of fatigue. In Y. Yatanabe, B. Evengard, B.H. Natelson, L.A. Jason, & H. Kuratsune (Eds.), Fatigue science for human health (pp 1–16). Springer. Jason, L.A., King, C. P., Richman, J.A., Taylor, R.R., Torres, S.R., & Song, S. (1999). U.S. case definition of chronic fatigue syndrome: Diagnostic and theoretical issues. Journal of Chronic Fatigue Syndrome, 5, 3–33. https://doi​.org​/10​.1300​/J092v05n03​ _02 Jason, L.A., Katz, B.Z., Sunnquist, M., Torres, C., Cotler, J., & Bhatia, S. (2020). The prevalence of pediatric myalgic encephalomyelitis/chronic fatigue syndrome in a community-based sample. Child & Youth Care Forum, 49, 563–579. https://doi​.org​/10​ .1007​/s10566​-019​-09543-3 Jason, L.A., Cotler, J., Islam, M., Sunnquist, M., & Katz, B.K. (2021). Risks for developing ME/CFS in college students following infectious mononucleosis: A prospective cohort study. Clinical Infectious Diseases, 73(11), e3740–e3746. https://doi.org/10.1093/cid/ ciaa1886.

30  Fatigue and Long-COVID Jason, L.A., Conroy, K.E., Furst, J., Vasan, K., & Katz, B.Z. (2022a). Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover. Molecular Omics, 18, 662–665. https://doi​.org​/10​.1039​/D2MO00124A Jason, L.A., Cotler, J., Islam, M.I., Furst, J., & Katz, B.Z. (2022b). Predictors for developing severe myalgic encephalomyelitis/chronic fatigue syndrome following infectious mononucleosis. Journal of Rehabilitation Therapy, 4(1), 1–5. https://doi​.org​/10​.29245​ /2767​-5122​/2021​/1​.1129 Jason, L.A., Kot, B., Sunnquist, M., Brown, A., Evans, M., Jantke, R., Williams, Y., Furst, J., & Vernon, S.D. (2015). Chronic fatigue syndrome and myalgic encephalomyelitis: Toward an empirical case definition. Health Psychology and Behavioral Medicine: An Open Access Journal, 3, 82–93. Jason, L.A., Richman, J.A., Rademaker, A.W., Jordan, K.M., Plioplys, A.V., Taylor, R.R., … & Plioplys, S. (1999). A community-based study of chronic fatigue syndrome. Archives of Internal Medicine, 159, 2129–2137. King, C., & Jason, L.A. (2005). Improving the diagnostic criteria and procedures for chronic fatigue syndrome. Biological Psychology, 68, 87–106. PMID: 15450690 Klein, J., Wood, J., Jaycox, J., Lu, P., Dhodapkar, R. M., Gehlhausen, J. R., Tabachnikova, A., Tabacof, L., Malik, A. A., Kamath, K., Greene, K., Monteiro, V. S., Peña-Hernandez, M., Mao, T., Bhattacharjee, B., Takahashi, T., Lucas, C., Silva, J., McCarthy, D., ... & Iwasaki, A. (2022). Distinguishing features of Long COVID identified through immune profiling. medRxiv. https://doi​.org​/10​.1101​/2022​.08​.09​.22278592 Lepow, M. L., Carver, D. H., Wright Jr, H. T., Woods, W. A., & Robbins, F. C. (1962). A clinical, epidemiologic and laboratory investigation of aseptic meningitis during the four-year period, 1955–1958: Observations concerning etiology and epidemiology. New England Journal of Medicine, 266(23), 1181–1187. Meeus, M., & Nijs, J. (2007). Central sensitization: A biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome [journal article]. Clinical Rheumatology, 26(4), 465–473. https://doi​.org​/10​.1007​/s10067​ -006​-0433-9 Moukaddam, N., & Shah, A. (2020). Psychiatrists beware! The impact of COVID-19 and pandemics on mental health. Psychiatric Times, 37(3). Nagy-Szakal, D., Barupal, D. K., Lee, B., Che, X., Williams, B. L., Kahn, E. J. R., Ukaigwe, J. E., Bateman, L., Klimas, N. G., Komaroff, A. L., Levine, S., Montoya, J. G., Peterson, D. L., Levin, B., Hornig, M., Fiehn, O., & Lipkin, W. I. (2018). Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Scientific Reports, 8(1), 10056–10056. https://doi​.org​/10​ .1038​/s41598​-018​-28477-9 National Achieves UK (2022) File MKC66/1 ME/CFS Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Department of Social Security, Summary of Talk by Professor P. K. Thomas, 2.11.93 (accessed 1st/9./2022) https://www.nationalarchives.gov.uk/ Picariello, F., Ali, S., Moss-Morris, R., & Chalder, T. (2015). The most popular terms for medically unexplained symptoms: The views of CFS patients. Journal of Psychosomatic Research, 78(5), 420–426. https://doi​.org​/10​.1016​/j​.jpsychores​.2015​.02​.013 Rivas-Vazquez, R. A., Rey, G., Quintana, A., & Rivas-Vazquez, A. A. (2022). Assessment and management of long COVID. Journal of Health Service Psychology, 48(1), 21–30. https://doi​.org​/10​.1007​/s42843​-022​-00055-8 Rubin, R. (2020). As their numbers grow, COVID-19 “Long Haulers” stump experts. JAMA, 324(14), 1381–1383. https://doi​.org​/10​.1001​/jama​.2020​.17709

Fatigue and Long-COVID  31 Sandler, C.X., Wyller, V.B.B., Moss-Morris, R., Buchwald, D., Crawley, E., Hautvast, J., Katz, B.Z., Knoop, H., Little, P., Taylor, R., Wensaas, K.A., & Lloyd, A.R. (2021). Long COVID and post-infective fatigue syndrome: A review. Open Forum Infectious Diseases, 8(10), ofab440. https://doi​.org​/10​.1093​/ofid​/ofab440. Scott, M. J., Crawford, J. S., Geraghty, K. J., & Marks, D. F. (2022). The 'medically unexplained symptoms' syndrome concept and the cognitive-behavioural treatment model. Journal of Health Psychology, 27(1), 3–8. https://doi​.org​/10​.1177​/13591053211038042 Sharpe, M. (1995). Cognitive behavior therapy for chronic fatigue syndrome. American Journal of Medicine, 98(4), 420–421; author reply 421-422. Siddaway, A. P. (2020). Multidisciplinary research priorities for the COVID-19 pandemic. Lancet Psychiatry, 7(7), e43. https://doi​.org​/10​.1016​/s2215​-0366(20)30220-0 Singh, I., Joseph, P., Heerdt, P. M., Cullinan, M., Lutchmansingh, D. D., Gulati, M., Possick, J. D., Systrom, D. M., & Waxman, A. B. (2022). Persistent exertional intolerance after COVID-19: Insights from invasive cardiopulmonary exercise testing. Chest, 161(1), 54–63. https://doi​.org​/10​.1016​/j​.chest​.2021​.08​.010 Smith, V. E. (2022). The secret files unwrapped: Part I – The importance of fair and accurate records. Retrieved October from https://valerieeliotsmith​.com​/2015​/01​/20​/the​-secret​ -files​-unwrapped​-part​-i​-the​-importance​-of​-fair​-and​-accurate​-records/ Stanley, I., Salmon, P., & Peters, S. (2002). Doctors and social epidemics: The problem of persistent unexplained physical symptoms, including chronic fatigue. The British Journal of General Practice: The Journal of the Royal College of General Practitioners, 52(478), 355– 356. https://www​.ncbi​.nlm​.nih​.gov​/pubmed​/12014530 Su, Y., Yuan, D., Chen, D.G., Ng, R.H., Wang, K., et al. (2022). Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. https://doi​.org​/10​.1016​/j​.cell​.2022​.01​.014 Taquet, M., Geddes, J. R., Husain, M., Luciano, S., & Harrison, P. J. (2021). 6-month neurological and psychiatric outcomes in 236  379 survivors of COVID-19: A retrospective cohort study using electronic health records. The Lancet Psychiatry, 8(5), 416–427. https://doi​.org​/10​.1016​/S2215​-0366(21)00084-5 Torjesen, I. (2022). NICE sets out steps NHS must take to implement ME/CFS guidelines. BMJ, 377, o1221. https://doi​.org​/10​.1136​/bmj​.o1221 Tsao, S.-F., Chen, H., Tisseverasinghe, T., Yang, Y., Li, L., & Butt, Z. A. (2021). What social media told us in the time of COVID-19: A scoping review. The Lancet Digital Health, 3(3), e175–e194. https://doi​.org​/10​.1016​/S2589​-7500(20)30315-0 Visser, D., Golla, S. S. V., Verfaillie, S. C. J., Coomans, E. M., Rikken, R. M., van de Giessen, E. M., den Hollander, M. E., Verveen, A., Yaqub, M., Barkhof, F., Horn, J., Koopman, B., Schober, P., Koch, D. W., Schuit, R. C., Windhorst, A. D., Kassiou, M., Boellaard, R., van Vugt, M., . van Berckel, B. N. M. (2022). Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. medRxiv, 2022.2006.2002.22275916. https://doi​.org​/10​.1101​/2022​.06​.02​.22275916 Watson, S., Ruskin, A., Simonis, V., Jason, L., Sunnquist, M., & Furst, J. (2014). Identifying defining aspects of chronic fatigue syndrome via unsupervised machine learning and feature selection. International Journal of Machine Learning and Computing, 4, 133–138. Wessely, S. (1994). Neurasthenia and chronic fatigue: Theory and practice in Britain and America. Transcultural Psychiatric Research Review, 31(2), 173–209. https://doi​.org​/doi​:10​ .1177​/136346159403100206 Wessely, S. (1997). Chronic fatigue syndrome: A 20th century illness? Scandinavian Journal of Work, Environment & Health, 23(Suppl 3), 17–34.

32  Fatigue and Long-COVID Wessely, S., David, A., Butler, S., & Chalder, T. (1989). Management of chronic (postviral) fatigue syndrome. The Journal of the Royal College of General Practitioners, 39(318), 26–29. http://www​.ncbi​.nlm​.nih​.gov​/pmc​/articles​/PMC1711569/ Wessely, S., Sharpe, M., & Hotopf, M. (1998). Chronic fatigue and its syndromes. Oxford University Press. White, P. D., Bruce-Jones, W. D., Thomas, J. M., Amess, J., & Clare, A. W. (1995). Viruses, neurosis and fatigue. J Psychosom Res, 39(3), 379. https://doi​.org​/10​.1016​/0022​ -3999(95)90133-7 Wormgoor, M.E.A., & Rodenburg, S.C. (2021). The evidence base for physiotherapy in myalgic encephalomyelitis/chronic fatigue syndrome when considering post‑exertional malaise: A systematic review and narrative synthesis. Journal of Translational Medicine, 19, 1. https://doi​.org​/10​.1186​/s12967​-020​-02683-4

Appendix A: A Questionnaire that Measures ME/CFS DePaul Symptom Questionnaire – Short Form

For each symptom below, please circle one number for frequency and one number for severity. Please complete the chart from left to right. Frequency

Severity

Throughout the past 6 months, how often have you had this symptom? For each symptom listed below, circle a number from: 0 = none of the time 1 = a little of the time 2 = about half the time 3 = most of the time 4 = all of the time

Throughout the past 6 months, how much has this symptom bothered you? For each symptom listed below, circle a number from: 0 = symptom not present 1 = mild 2 = moderate 3 = severe 4 = very severe

Symptom

Frequency

Severity

1. Fatigue/extreme tiredness 2. Next day soreness or fatigue after nonstrenuous, everyday activities 3. Minimum exercise makes you physically tired 4. Feeling unrefreshed after you wake up in the morning 5. Pain or aching in your muscles 6. Bloating 7. Problems remembering things

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

Fatigue and Long-COVID  33 8. Difficulty paying attention for a long period of time 9. Irritable bowel problems 10. Feeling unsteady on your feet, like you might fall 11. Cold limbs (e.g. arms, legs, hands) 12. Feeling hot or cold for no reason 13. Flu-like symptoms 14. Some smells, foods, medications, or chemicals make you feel sick

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

0 1 2 3 4 0 1 2 3 4

Appendix B: A Questionnaire that Measures Post-Exertional Malaise DePaul Symptom Questionnaire Post-Exertional Malaise

For each symptom below, please circle one number for frequency and one number for severity. Please complete the chart from left to right. Frequency

Severity

Throughout the past 6 months, how often have you had this symptom? For each symptom listed below, circle a number from: 0 = none of the time 1 = a little of the time 2 = about half the time 3 = most of the time 4 = all of the time

Throughout the past 6 months, how much has this symptom bothered you? For each symptom listed below, circle a number from: 0 = symptom not present 1 = mild 2 = moderate 3 = severe 4 = very severe

Symptom

Frequency

Severity

1. Dead, heavy feeling after starting to exercise 2. Next day soreness or fatigue after nonstrenuous, everyday activities 3. Mentally tired after slightest effort 4. Minimum exercise makes you physically tired 5. Physically drained or sick after mild activity

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

0 1 2 3 4

34  Fatigue and Long-COVID Symptom

Circle one

6. If you were to become exhausted after actively participating in extracurricular activities, sports, or outings with friends, would you recover within an hour or two after the activity ended? 7. Do you experience a worsening of your fatigue/energy-related illness after engaging in minimal physical effort? 8. Do you experience a worsening of your fatigue/energy-related illness after engaging in mental effort? 9. If you feel worse after activities, how long does this last?

Yes No

10. If you do not exercise, is it because exercise makes your symptoms worse?

Yes No Yes No Less than 1hour 2–3 hours 4–10 hours 11–13 hours 14–23 hours 24 hours or more Yes No

3

Neurocognitive Disorders Elizabeta B. Mukaetova-Ladinska, MD, Ph.D., Stella Paddick, MD, Ph.D., and Akram A. Hosseini, MD, Ph.D.

The COVID-19 pandemic’s unique psychosocial impact (i.e. reduction in social engagements, lifestyle changes, and psychological reaction) raises concern regarding its possible effect on cognition, high levels of stress, anxiety, and depression. An online survey of highly educated older adults after 1 year of COVID-19-restrictions found a high rate (74%) of at least one unfavorable impact of lifestyle change on participants’ mental health with loneliness, sleep problems, and less physical activity being most frequently reported (Waterlink et al., 2022). These modifiable risk factors suggest that some individuals may be more vulnerable to the impact of disease-induced social isolation and provide an opportunity to develop and put in place a timely targeted prevention and education to promote a healthy lifestyle during and after the pandemic and future similar events. People with already known dementia also exhibited additional worsening of both their cognitive function and behavior (i.e. agitation, depression, anxiety, and changes in appetite), and difficulties accessing medical care, with their caregivers reporting an increased burden and burnout. This has been confirmed in the more recent systematic review/meta-analysis on 7,139 patients assessed 5.6 weeks/mean post-lockdown, that confirmed increased neuropsychiatric symptoms in both people with dementia and mild cognitive impairment (MCI) following COVID-19 lockdown (Soysal et al., 2022). In this book chapter, we critically review the clinical evidence for cognitive impairment post-COVID-19 infection from both cross-sectional and longitudinal studies, and the role of delirium in raising the risk for cognitive impairment in both younger and older people affected with the SARS-CoV-2 infection. For this, we enlisted the expertise of clinical psychiatry and neurology specialists in the field, working with both younger and older people with minor and major cognitive impairments.

Susceptibility and Vulnerability to Neurocognitive Impairment in COVID-19 The neurotropic properties of the SARS-CoV-2 virus and its ability to involve the central nervous system have resulted in increased interest in the Covid-19 DOI: 10.4324/9781003371090-3

36  Neurocognitive Disorders

contribution to neurocognitive impairment: COVID-19 and dementia, in particular Alzheimer’s disease, share a number of common risk factors and comorbid conditions including age, sex, hypertension, diabetes, and higher prevalence of APOE ε4 (Livingston et al., 2020). A low-grade inflammation has similarly been associated both with depression and cognitive symptoms (Gialluisi et al., 2020), suggesting a link between even mild viral infection and cognitive impairment. Genetic makeup and causal risk factors (i.e. various lifestyle factors, environmental chemicals, adverse life events, etc.) should also be considered in modulating the overall risk of neurocognitive impairment (Figure 3.1), alongside the known predisposing risk factors to the infection, i.e. female gender, older age, low socio-economic status (which impedes people’s cognitive capacity and lifestyle choices, i.e. alcohol, smoking, illicit substance use, lack of exercise, poor diet, sedentary lifestyle, late presentations to healthcare providers, etc.). The lifestyle choices and the low socio-economic status also lead to an increased exposure to the virus, higher stress and comorbidities associated with poverty (i.e. hypertension, diabetes, cardiovascular illnesses, respiratory and liver diseases, etc.), and reduced access to health care, which all may contribute to the emerging neurocognitive deficit immediately postinfection, or as a part of the long-COVID-19 syndrome. However, the premorbid cognitive reserve appears to modulate the impact of these variables on cognition, with cognitive complaints experienced in people with high cognitive reserve being related to anxiety but not cognitive performance (CostasCarrera et al., 2022).

COVID-19 pandemic

SARS-CoV-2 infection

Neurotropic mechanism Thromboembolic and haemorrhagic (hypoxic) events Genetics Gut-lung-brain diathesis Polyorgan failure Autommune mechanism

No evolution toward cognitive impairment

Delirium

Neurocognitive impairment

COVID-19 policies induced pandemicassociated psychosocial stressors

Social isolation Change in lifestyle Restricted access to medical care Increase in alcohol/drug intake Sleep problems Lack of physical activity

Figure 3.1 Schematic representation of COVID-19 pandemic influencing cognitive impairment (modified after Manca et al., 2020 to accommodate current review).

Neurocognitive Disorders  37

Delirium and Cognitive Impairment Post-COVID-19 Infection Delirium is a common complication in COVID-19. A large multi-country study reported >50% prevalence of delirium. Notably family visitation (often prevented by pandemic regulations) reduced delirium by 30% (Pun et al., 2021). A systematic review reported pooled prevalence and incidence of 24.3% and 32.4% respectively and a three-fold increase in mortality in COVID-19 patients with delirium (Shao et al., 2021). Adult respiratory distress syndrome (ARDS) is frequent in severe COVID19 and can result in delirium, cognitive impairment (predominantly impaired executive function and short-term memory), anxiety, and depression. A previous study on ARDS (not related to COVID-19) outcomes reported very high cognitive impairment prevalence (70–100%) at hospital discharge, 46–80% at 1 year, and 20% at 5 years post-discharge (Herridge et al., 2016). Likely risk factors for consequent cognitive impairment are pre-existing cognitive impairment, sepsis, mechanical ventilation, prolonged use of sedative medications, Systemic inflammation, and intensive care unit (ICU)-environmental factors. The pre-existing chronic blood brain barrier damage from Alzheimer’s disease pathology may be compounded by acute brain blood barrier damage due to mechanical ventilation and/or acute inflammatory response, leading to neuronal damage mediated by cytokines and accumulation of amyloid beta. Among COVID-19 patients with delirium during hospitalization, 23% had questionable cognitive impairment or cognitive impairment consistent with dementia 2 months later (Ragheb et al., 2021). The brief follow-up period (2 months) unsurprisingly resulted in a quarter of patients continuing to have delirium, though the subtype of delirium was not specified. However, half of the ICU patients in this study had agitation during their inpatient delirious episode, suggesting that they may well have had a hyperactive delirium at that time. This may have also contributed to the low prevalence rate of cognitive impairment at follow-up, since the hypoactive subtype of delirium is associated with more severe cognitive impairment compared with the hyperactive type. That infection and host inflammatory response contribute to Covid-19 associated neurocognitive impairment was confirmed in a systematic review (6 studies, 644 participants, mean age 61 years; Alnefeesi et al., 2021). In this study, the most common cognitive impairment was related to the presence of delirium, accompanied by elevated inflammatory markers, i.e. IL-6, TNF-α, and IL-1β and cytokines, known to impact working memory and attention. Although the outcomes from ICU treated patients are somewhat inconclusive, another study demonstrated that thrombo-inflammation biomarkers and low Horowitz/Carrico index may negatively impact cognitive performance 6 months after hospital discharge in adult COVID-19 patients (García-Grimshaw et al., 2022), highlighting the critical role of hypoxemia, and not delirium alone, as a driver for impaired cognition following covid infection. Similar findings were reported by Weidman et al., 2022, who found that cognitive impairment was unrelated to delirium, length of ICU stay, or pharmacological

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treatment. This suggests that the management of ICU COVID patients may differ. Thus, deviation from delirium prevention protocols, under-diagnosis of delirium, lack of regular use of approved screening delirium tools, heterogeneity of delirium management, and presence of cerebrovascular events all have an impact on the long-term outcomes of delirium. Delirium studies involving older people are still sparse, despite delirium being common (25–50%) among older people with COVID-19 infection, with hypoactive being the most predominant subtype (41.6%), followed by hyperactive (35.4%) and mixed (23.0%) subtypes (Mendes et al., 2021). Age over 65 years increases the likelihood of developing delirium during SARS-CoV-2 infection by nearly 9-fold (LaHue et al., 2022), an odds ratio that is similar to that reported in population epidemiological studies on aged ≥85 years people who were not exposed to viral infection (Davies et al., 2012). Although this suggests that SARS-CoV-2-induced delirium may have similar cognitive consequences to delirium resulting from more common precipitants in older people, it is the severity of illness requiring ICU treatment that contributes to neurocognitive deterioration in somewhat young-old people (65–81 years) (LeHue et al., 2022). These reports highlighted that it was delirium, COVID-19 severity, and COPD that were risk factors for cognitive impairment, alongside low education level and hypertension contributing to longitudinal cognitive decline (Liu et al., 2021), suggesting that older COVID-19 patients, especially those with severe infection, should be intensively monitored for post-infection cognitive decline. Delirium can also be an isolated, if not a sole clinical manifestation of COVID-19 infection, especially in older people with pre-existing mild cognitive impairment (Fabrazzo et al., 2022). This study was based on three inpatient case reports, and we cannot exclude the possibility that similar clinical scenarios may have occurred in the general older population, with an acute confusional state being the only manifestation of COVID-19 infection, leading to further cognitive sequelae. The lack of longitudinal follow-up and detailed clinical information is another pitfall regarding the generalizability of these findings. A further complicating factor is post-traumatic stress disorder (PTSD), known to increase the risk of cognitive decline and dementia. PTSD commonly occurs post-delirium and ICU/critical care admission. The delirium appears to be increased in individuals with ARDS (>30%) or requiring mechanical ventilation (Kaseda and Levine, 2020). PTSD prevalence appears to be relatively stable in both non-hospitalized (7%) and hospitalized (9.5%) patients (Einvik et al., 2021), and remains so 3 months post-recovery from COVID-19 hospitalization (10.2%, Tarsitan et al., 2021). However, PTSD prevalence may be higher (16%) in the context of severe COVID-19 infection and prolonged (>4 weeks) post-infection recovery (Nagarajan et al., 2022).

COVID-19 and Persistent Cognitive Impairment Long Covid or post-acute sequelae of COVID-19 (PASC) refers to long-term symptoms occurring in individuals with a history of probable or confirmed

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SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms lasting for at least 2 months which cannot be explained by an alternative diagnosis (WHO, 2021). Among the common symptoms (fatigue, shortness of breath, cardiovascular, gastrointestinal, ear, nose and throat, dermatological and musculoskeletal symptoms, pain), neurological and mental disorders (anxiety, depression, and PTSD) are also reported. These may all occur as new onset symptoms, following recovery from acute SARS-CoV-2 infection, or persist from the beginning of the infection, and can fluctuate or relapse over time. According to this definition, Long Covid cognitive impairment encompasses both minor and major neurocognitive impairments. Persistent subjective and objective cognitive impairments post-COVID-19 infection appear common. Up to 17–19% of COVID-19 patients have cognitive impairment (Rogers et al., 2020, PHOSP Covid Collaborative Group, 2022). In a recent meta-analysis, pooled prevalence at >3 months postCOVID-19 was 36% for objective and 18% for subjective cognitive impairment. Prevalence in hospitalized (30%) vs non-hospitalized (20%) samples was not statistically significant and did not differ between individuals assessed 6 months post-infection (Ceban et al., 2022). SARS-CoV-2 infection may re-activate viral co-infection, especially human immunodeficiency and Epstein–Barr viruses, resulting in Long COVID-19 symptoms with predicted distinct syndromic patterns, i.e. neurocognitive deficit. SARS-CoV-2 viral reservoirs have similarly been found in human organs, i.e. gut and lower gastrointestinal tract, months after infection onset, thus raising the hypothesis that ongoing infection may result in Long Covid. In addition, multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma and widespread endothelial cell activation have been documented post-mortem, and may contribute to similar immune responses in patients with Long Covid leading to widespread neuronal loss, underlying major cognitive impairment/dementia. Although subjective and objective cognitive impairments are well-recognized post-COVID-19 infection, the comparison and synthesis of data are challenging. Heterogeneity and timing of cognitive assessments, severity of infection, serological confirmation of COVID-19 in study participants alongside discourse in treatment (i.e. ambulatory, ICU) make the available findings difficult to interpret and compare. Most studies measure cognitive impairment acutely or post-acutely, resulting in challenges in the differentiation of observed deficits from delirium and PTSD sequelae. Moreover, the majority of studies utilize only brief cognitive measures i.e. Montreal Cognitive Assessment (MOCA) and Mini Mental State Examination (MMSE), limiting understanding of specific cognitive domains that may be affected following COVID-19 infection. A recent scoping review of 25 studies found that neurological and respiratory conditions, but not ICU admission, were associated with cognitive deficits in subjects evaluated 3–6 months post-infection. The most affected cognitive domains were memory, attention, and executive functions (including

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abstraction, inhibition, set shifting, and sustained and selective attention), with delayed recall and learning being the most impaired, whereas language and visuo-spatial abilities were rarely affected (Bertuccelli et al., 2022). Few included studies reported on visuospatial or language impairment. Similarly, a systematic review of serologically confirmed COVID-19 found that memory, attention, and executive function were most affected, with the most prominent deficit in processing speed, executive function, phonemic and category fluency, memory encoding, and recall (Crivelli et al., 2022). The fact that “gross” impairment (equating to one point loss on the MOCA) was detectable at >6 months post-infection in this younger sample may explain the high neurocognitive prevalence reported in other studies. One of the largest and most detailed cognitive outcome studies was that based on the Great British Intelligence Test (GBIT) where >80,000 UK residents self-administered a detailed and broad neuropsychological test battery allowing comparison with normative values. Of those self-reporting previous COVID-19 infection, there was a clear negative trajectory of global cognitive impairment from mildly symptomatic to ventilated based on respiratory symptoms. COVID-19 infection appeared to have a greater effect on executive type tasks of reasoning, problem-solving, and planning compared to simpler “working memory” tasks though these are often classified also as executive functions (Hampshire et al., 2021). Poletti et al. ((2022) found no significant difference in cognitive performance using the Brief Assessment of Cognition in schizophrenia, in 3 separate cohorts (4 points greater than previous non-pandemic decline) compared to 2% of seronegative persons (del Brutto et al., 2021) – 18-fold increased odds of cognitive decline in the seropositive group. In contrast, a small study of people with baseline neurological disease found a high prevalence of memory impairment (68.8%) and decreased concentration (61.5%), but their average MOCA scores improved overall, though 26.3% of participants declined at 6-months follow-up (Shanley et al., 2022). Frontera et al. (2022) reported on cognition, depression, fatigue, and sleep in 242 patients 6 and 12-months post-infection and reported 50% to have lower tele-MOCA scores at 12 months. However, there was a significant improvement (56%) in cognitive outcome from 6 to 12 months, but not in sleep pattern and depression. It is worth stressing that worsening cognition was reported in 28% of participants compared to 25 and 28% for anxiety and depression respectively. The latter figures are similar to the greater prevalence of anxiety and depression prevalence at 12 months follow-up (Huang at al., 2021). In a study on non-hospitalized COVID patients, cognitive impairment (measured with MOCA) was reported in 56% at 3 months, reducing to 41% at 6–7 months follow-up. The reported improvement was just one MOCA point, whereas the prevalence of moderate-severe anxiety and depression (defined as Hospital Anxiety and Depression Scale (HADS) >13) remained

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unchanged, with 45% and 46% of the examined sample continuing to report these symptoms throughout the follow-up period (Del Corral et al., 2022). The longest study to date was conducted over 18 months, with 78 participants (50 with a history of mild COVID-19 and 28 without) cognitively evaluated at 4 time points (2 cognitive assessments before and 6 and 18 months after the initial SARS-CoV-2 outbreak; Del Brutto et al., 2022). There was an age-related decline in MOCA scores between the two pre-pandemic tests. Six months after infection, only COVID-19 survivors had a significant decline in MOCA scores, which reversed after one additional year of follow-up, a pattern not observed among the noninfected individuals. This study suggests that long COVID-related cognitive decline may spontaneously improve over time. However, when using a more detailed cognitive battery which consists of five subtests to assess verbal learning and fluency, working memory, delayed memory and processing speed, and Trail Making Test-part 1A and B, the trajectory of cognitive functions from 3 months to 1 year after COVID-19 hospitalization indicated that patients with impaired cognition 3 months after hospitalization do not improve after 1 year, while patients with no impairments after 3 months remain cognitively intact (Miskowiak et al., 2022). This study found a high prevalence of stable cognitive impairment (46%–59%). The trajectory based on 2 years retrospective data similarly proved that the increased incidence of mood and anxiety disorders was transient, whereas the increased risk of psychotic disorder, cognitive deficit (“brain fog”), and dementia, for both adults and older people, persisted throughout (Taquet et al., 2022). The cognitive outcomes were similar during the delta and omicron waves, indicating that the potential health-care system burden might continue even with variants considered less severe in other respects. The unstable cognitive profile post-COVID bears resemblance to the one described in HIV-infected adults followed over 4 years. Namely, HIV-associated neurocognitive disorders (HAND) remained stable in 54%, improved in 15%, and declined in 31%, with older age and lower education level significantly predicting HAND progression, whereas male sex and shorter combination antiretroviral therapy (cART) duration were associated with improvement (Spooner et al., 2022).

Covid and Mental Wellbeing of Older Adults Current available evidence suggests that the COVID-19 pandemic negatively impacts the mental wellbeing of older adults irrespective of their baseline cognitive functioning. Thus, a systematic review of older people with COVID19 infection and those exposed to pandemic-related enforced social isolation found high rates of reported delirium accompanied by agitation and apathy, especially in people with dementia (Manca et al., 2020). A comparative study on cognitive trajectories (using MMSE/tele-MMSE) prior to and during the pandemic reported an accelerated decline in older adults (Amieva et al., 2022). The incidence of cognitive impairment in older COVID-19 survivors 12 months after discharge was 12.45% (Liu et al., 2022), with worse cognition

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reported in those with a severe infection. Severe COVID-19 increased the risk of both early- and late-onset cognitive and progressive cognitive decline, while non-severe COVID-19 was associated with a higher risk of early-onset cognitive decline. A follow-up of 1,755 older people 1 year post-COVID-19 infection reported similar dementia incidence (12.7%), with pre-COVID psychotropic medication use and delirium contributing to a 3-fold increase of post-COVID dementia (Freudenberg-Hua et al., 2022). Poor dietary intake occurring during the pandemic may contribute to worsening physical status. Poor nutritional status was associated with increased age, comorbidity burden, frailty, immobility, impaired basic activities of daily living, history of falls, cognitive impairment, incontinence, and arthritis in elders, resulting in further health deterioration and even death. It is, therefore, not surprising that older people with dementia show similar physical deterioration in COVID-19 infection, with the most common symptoms at COVID-19 onset being confusion and delirium (82%) and asthenia (77%) with half of them having breathing problems and falls (35%) (Vrillon et al., 2021).

Treatment Strategies and Cognitive Rehabilitation in Long-COVID Syndrome Understanding the molecular pathogenesis of SARS-CoV-2 infection leading to cognitive impairment, either alone or accompanied by additional neuropsychiatric symptoms, is crucial for its treatment. This may require either the repositioning of currently available pharmacotherapies or devising novel ones, targeting leading clinical post-COVID sequelae. Since the majority of patients have minor cognitive impairment largely secondary to depression, anxiety, and fatigue, addressing them alone may help improve the neurocognitive changes in these patients. In addition, serotonin reduces cytokine overproduction under severe and systemic inflammatory conditions, including those caused by COVID-19 (Takenaka et al., 2022). This can help reduce the long-term COVID-19 sequelae, including depression, anxiety, and cognitive impairment. Indeed, some of the selective serotonergic inhibitor antidepressant medication, i.e. fluoxetine, fluvoxamine, and sertraline, have been found to have anti-inflammatory and anti-viral properties in COVID-19 patients, and may be used as an adjunct therapy for this condition (Takenaka et al., 2022). The rehabilitation and treatment options for fatigue include a structured and phased return to activity program, energy conservation strategies, healthy dietary pattern and hydration, and treatment in combination with specialist approaches for background medical conditions and psychiatric issues/symptoms contributing to fatigue. Pharmacological therapy and supplements, such as branched-chain amino acids, omega 3 fatty acids, vitamin B12, vitamin C, vitamin D, magnesium, L-carnitine, coenzyme Q10, ginseng, echinacea, and many others, have been suggested to improve fatigue in other chronic illness and support the immune system, alleviate inflammation, and improve fatigue.

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Medications including amantadine, modafinil, and methylphenidate that can be used for fatigue in other conditions (such as chronic fatigue syndrome, multiple sclerosis, Parkinson’s disease, traumatic brain injuries) can be prescribed for fatigue due to PASC (Farooqi et al., 2022). There are suggestions to utilize other medications that have been tried for the treatment of chronic fatigue syndrome including antivirals, antimicrobials or antiparasitics, antidepressants, cytokine inhibitors, galantamine, corticosteroids, intravenous immunoglobulins, and rituximab. There is currently no evidence of these treatments for patients with PASC. A multidisciplinary rehabilitation program including pulmonary, cardiovascular, and neuropsychological interventions is recommended to start during the in-patient setting and continue following hospital discharge. These rehabilitation programs should also focus on outpatient multidisciplinary approaches to improve functional and cognitive outcomes. There have been several psychological intervention trials to improve neuropsychiatric symptoms, cognitive function, and quality of life following COVID-19. These include self-management programs. Some trials exclude patients with severe or acute or previous mental health illness or significant cognitive impairment. Pharmacological agents such as vortioxetine (a recombinant C1 esterase inhibitor in improving neurological symptoms in Post-SARS-CoV-2 infection, with similar effectiveness to other antidepressants) and atorvastatin (used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels) focus on cognitive function and are not integrated models of care. Portable oxygen concentrators and a one-time marrow stromal cell infusion are other medical interventions that focus on cognitive and other functions and mood. Trials of cannabidiol-dominant medicinal cannabis, Vitamin B3, and some combinations of homeopathic medicine, mixed herbal supplements, Chinese herbal medicine, and dietary replacement with a weight management program examine mental health, cognitive, Long COVID symptoms, and quality-of-life outcomes. A number of trials test improving cognitive outcomes and neurorehabilitation using cognitive training and brain stimulation. Although physiotherapy rehabilitation programs focus on respiratory or cardio-respiratory rehabilitation, they can also result in improvement in cognitive function. Some studies combine individualized exercise with cognitive training (updated information on ongoing clinical trials on: https://clinicaltrials​ .gov​/ct2​/covid​_view).

Conclusion All the findings so far suggest that the cognitive impairment post-COVID-19 infection for most of patients is transient, with on average 20%–25% continuing to experience some cognitive deficit after 12–18 months. However, this seems not to reach the major cognitive impairment threshold, and it is largely associated with the COVID-19 infection severity, physical frailty, persistent fatigue, and depressive psychopathology at the time of infection.

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The design of the studies also makes it difficult to compare the findings. Most of the reported studies to date used a brief cognitive assessment, the MOCA, whereas only a minor number of studies performed more detailed cognitive assessments, that pointed to either no significant change over time or the presence of dysexecutive syndrome. However, these studies were conducted on a relatively smaller sample size, and need to be reproduced for their findings to be generalized. In addition, neuropsychological assessment and/or self-reported scales of mental health and physical health were used, with the baseline, premorbid information often missing. This could have contributed to under-/over-reporting of cognitive impairment. Even studies conducted in ICU patients failed to take into account the presence of delirium, or the presence of subsyndromal delirium after discharge that could have an impact on the cognitive performance. If this is the case, this could have contributed to the cognitive improvement reported in patients 3–6 months post-infection. The reported rather consistent presence of anxiety and depression in onequarter of post-COVID patients after 1 year seems to be consistent with the percentage of cognitive worsening in these population. In the absence of longer duration studies, it is difficult to predict how many of these patients may be at a higher risk of developing incident dementia long-term, with the affective dysregulation being a predementia risk factor. Namely, mild behavioral impairment describes later life acquired, sustained neuropsychiatric symptoms in cognitively normal individuals or those with MCI, and is considered to be an at-risk state for incident cognitive decline and dementia. The abundance of newly sustained neuropsychiatric symptoms with the COVID-19 pandemic, either as a direct result of infection or psychosocial impact, alongside the increased prevalence of anxiety and depression, as documented in this review, also results in minor cognitive impairment, that in some instances, especially in younger people, can be transient. However, 20% of the affected adults have remaining overt cognitive problems. Exploring the potential heterogeneity of the complex constellation of affective symptoms, adverse life events, severity of SARS-CoV-2 infection, and outcomes may help model all potential interactions between them and define distinct cognitive profiles. The highly contagious COVID-19 infection required not only adaptation in the way clinical services are delivered, but led to the enrichment of our routine cognitive assessments, bringing on advances in intelligent telemedicine that have been accepted well by both service users and providers. It also provides a unique opportunity at a molecular level to investigate in depth how cognitive impairment evolves and progresses (either to overt cognitive impairment, stalls at the stage of “brain fog,” or restores back to baseline cognitive functioning). These crude milestones have the potential for devising and implementing diagnostic tool(s) and therapeutics for distinct forms of neurocognitive impairment, i.e. subjective, functional, minor, or major cognitive impairment.

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50  Neurocognitive Disorders Miskowiak, K. W., Fugledalen, L., Jespersen, A. E., Sattler, S. M., Podlekareva, D., Rungby, J., Porsberg, C. M. & Johnsen, S. (2022). Trajectory of cognitive impairments over 1 year after COVID-19 hospitalisation: Pattern, severity, and functional implications. European Neuropsychopharmacology, 59, 82–92. Nagarajan, R., Krishnamoorthy, Y., Basavarachar, V. & Dakshinamoorthy, R. (2022). Prevalence of post-traumatic stress disorder among survivors of severe COVID-19 infections: A systematic review and meta-analysis. Journal of Affective Disorders, 299, 52–59. Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G. & Kokmen, E. (1999). Mild cognitive impairment: Clinical characterization and outcome. Archives of Neurology, 56, 303–308. PHOSP-COVID Collaborative Group. (2022). Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: A prospective observational study. Lancet Respiratory Medicine, 10(8), 761–775. Poletti, S., Palladini, M., Mazza M. G., De Lorenzo, R., The COVID-19 BioB Outpatient Clinic Study Group, Furlan, R., Ciceri, F., Rovere-Querini, P. & Benedetti, F. (2022). Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life. European Archives of Psychiatry and Clinical Neuroscience, 272, 773–782. Pun, B. T., Badenes, R., La Calle, G. H., Orun, O. M., Chen, W., Raman, R., Simpson, B. G., Wilson-Linville, S., Olmedillo, B. H., de la Cueva, A. V. & van der Jagt, M. (2021). Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study. The Lancet Respiratory Medicine, 9(3), 239–250. Ragheb, J., McKinney, A., Zierau, M., Brooks, J., Hill-Caruthers, M., Iskander, M., Ahmed, Y., Lobo, R., Mentz, G, & Vlisides, P. E. (2021). Delirium and neuropsychological outcomes in critically ill patients with COVID-19: A cohort study. British Medical Journal Open, 11(9), e050045. Rogers, J. P., Chesney, E., Oliver, D., Pollak, T. A., McGuire, P., Fusar-Poli, P., Zandi, M. S., Lewis, G. & David, A. S. (2020). Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry, 7(7), 611–627. Shanley, J. E., Valenciano, A. F., Timmons, G., Miner, A. E., Kakarla, V., Rempe, T., Yang, J. H., Gooding, A., Norman, M. A., Banks, S. J., Ritter, M. L., Ellis, R. J., Horton, L. & Graves, J. S. (2022). Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms. Annals of Clinical and Translational Neurology, 9(7), 995–1010. Shao, S. C., Lai, C. C., Chen, Y. H., Chen, Y. C., Hung, M. J. & Liao, S. C. (2021) Prevalence, incidence and mortality of delirium in patients with COVID-19: A systematic review and meta-analysis. Age Ageing, 50(5), 1445–1453. Soysal, P., Smith, L., Trott, M., Alexopoulos, P., Barbagallo, M., Tan, S. G., Koyanagi, A., Shenkin, S., Veronese, N. & European Society of Geriatric Medicine Special Interest Group in Dementia and Systematic Reviews and Meta-Analyses. (2022). The Effects of COVID-19 lockdown on neuropsychiatric symptoms in patients with dementia or mild cognitive impairment: A systematic review and meta-analysis. Psychogeriatrics, 22(3), 402–412. Spooner, R., Ranasinghe, S., Urasa, S., Yoseph, M., Koipapi, S., Mukaetova-Ladinska, E. B., Lewis, T., Howlett, W., Dekker, M., Kisoli, A., Gray, W. K., Walker, R. W., Dotchin, C. L., Kalaria, R., Lwezuala, B., Makupa, P. C., Akinyemi, R. & Paddick, S. M. (2022). HIV-associated neurocognitive disorders: The first longitudinal follow-up of

Neurocognitive Disorders  51 a cART-treated cohort of older people in Sub-Saharan Africa. Journal of Acquired Immune Deficiency Syndromes, 90(2), 214–222. Takenaka, Y., Tanaka, R., Kitabatake, K., Kuramochi, K., Aoki, S. & Tsukimoto, M. (2022) Profiling differential effects of 5 selective serotonin reuptake inhibitors on TLRsdependent and -independent IL-6 production in immune cells identifies fluoxetine as preferred anti-inflammatory drug candidate. Frontiers in Pharmacology, 13, 874375. Taquet, M., Sillett, R., Zhu, L., Mendel, J., Camplisson, I., Dercon, Q. & Harrison, P. J. (2022). Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: An analysis of 2-year retrospective cohort studies including 1284437 patients. Lancet Psychiatry, S2215- 0366(22), 00260–7. Tarsitani, L., Vassalini, P., Koukopoulos, A., Borrazzo, C., Alessi, F., Di Nicolantonio, C., Serra, R., Alessandri, F., Ceccarelli, G., Mastroianni, C. M. & d’Ettorre, G. (2021). Post-traumatic stress disorder among COVID-19 survivors at 3-month follow-up after hospital discharge. Journal of General Internal Medicine, 6(6), 1702–1707. Valdes, E., Fuchs, B., Morrison, C., Charvet, L., Lewis, A., Thawani, S., Balcer, L., Galetta, S. L., Wisniewski, T., Frontera, J. A. (2022). Demographic and social determinants of cognitive dysfunction following hospitalization for COVID-19. Journal of Neurological Sciences, 38, 120146. Vannorsdall, T. V., Brigham, E., Fawzy, A., Raju, S., Gorgone, A., Pletnikova, A., Lyketsos, C. G., Parker, A. M. & Oh, E. S. (2022) Cognitive dysfunction, psychiatric distress, and functional decline after COVID-19. Journal of the Academy of ConsultationLiaison Psychiatry, 63(2), 133–143. Vialatte de Pémille, C., Ray, A., Michel, A., Stefano, F., Yim, T., Bruel C. & Zuber M. (2022). Prevalence and prospective evaluation of cognitive dysfunctions after SARS due to SARS-CoV-2 virus. The COgnitiVID study. Revue Neurologique. S0035-3787(22)00616-6. Vrillon, A., Mhanna, E., Aveneau, C., Lebozec, M., Grosset, L., Nankam, D., Albuquerque, F., Razou Feroldi, R., Maakaroun, B., Pissareva, I., Cherni Gherissi, D., Azuar, J., François, V., Hourrègue, C., Dumurgier, J., Volpe-Gillot, L. & Paquet, C. (2021). COVID-19 in adults with dementia: Clinical features and risk factors of mortality-a clinical cohort study on 125 patients. Alzheimer's Research & Therapy, 13(1), 77. Waterink, L., Bakker, E. D., Visser, L. N. C., Mangialasche, F., Kivipelto, M., Deckers, K., Köhler, S., Sietske, A. M., Sikkes, S. A. M., Prins, N. D., Scheltens, P., van der Flier, W. M. & Zwan, M. D. (2022). Changes in brain-health related modifiable risk factors in older adults after one year of COVID-19-restrictions. Frontiers in Psychiatry, 13, 877460. Weidman, K., LaFond, E., Hoffman, K. L., Goyal, P., Parkhurst, C. N., Derry-Vick, H., Schenck, E. & Lief, L. (2022). Post-intensive care unit syndrome in a cohort of COVID19 survivors in New York City. Annals of the American Thoracic Society, 19(7), 1158–1168. Weihe, S., Mortensen, C. B., Haase, N., Andersen, L. P. K., Mohr, T., Siegel, T., Ibsen, M., Jørgensen, V. R. L., Buck, D. L., Pedersen, H. B. S., Pedersen, H. P., Iversen, S., Ribergaard, N., Rasmussen. B. S., Winding, R., Espelund, U. S., Bundgaard, H., Sølling, C. G., Christensen, S., Garcia, R. S., Brøchner, A. C., Michelsen, J., Michagin, G., Kirkegaard, L., Perner, A., Mathiesen, O. & Poulsen, L. M. (2022). Long term cognitive and functional status in Danish ICU patients with COVID-19. Acta Anaesthesiologica Scandinavica, 66(8), 978–986. WHO Organization. (2021). A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. www​.who​.int​/publications​/i​/item​/WHO​-2019​ -nCoV​-Post​_COVID​-19​_condition​-Clinical​_case​_definition​-2021.1

4

Brain and Nervous System Sudhir Mehta, MD, FAMS, FRCP (London & Edin), FACP, FICP, Gaurav Jain, MBBS DNB MNAMS, and Varun Jain MD

The management of COVID-19 with a high infectivity rate and a variety of clinical manifestations involving different organ systems has been difficult not only for general physicians and intensivists but also for neurologists. COVID-19 is known to cause fearful respiratory complication, but its neurological implications like stroke, venous sinus thrombosis, encephalitis, and acute sensorimotor neuropathies have also led to increased morbidity and mortality. While the coronavirus pandemic was raging all over, scientists were trying to find the cure. A few months after the declaration of the pandemic, there were anti-viral agents developed with significant good results. In less than one year’s duration, pharmaceutical manufacturers in the United States of America were able to develop a vaccine for coronavirus which helped in bending the ever-ascending curve of coronavirus-related mortality. Later, due to global coordination, widespread vaccination was facilitated. In addition to vaccination, the development of herd immunity in the society helped in blunting the critical outcomes of this devastating pandemic. Although the patients with pure and critical neurological dysfunction from COVID-19 infection are very few, the neurological disease burden is seen to be high in patients who continue to have lingering symptoms over a long period of time affecting their quality of life. We are now facing the daunting task of dealing with the long-term mental health and neurological complications in coronavirus patients. It has so far appeared to be a challenging task as none of us had considered the possibility of the persistence of symptoms for weeks and months beyond recovery from the initial infection. Studies have shown that many symptoms of coronavirus infection can persistent for months in a significant number of patients despite the recommended treatment by the Food and Drug Administration (FDA) and the World Health Organization (WHO). This results in adversely affecting their quality of life. This issue has now become the center of attention of medical health care professionals, and we are still struggling to understand and manage it in a better way.

DOI: 10.4324/9781003371090-4

Brain and Nervous System  53

Long COVID-Neurological Aspects The purpose of this chapter is to learn about the neurological manifestations of Long COVID along with their pathophysiology and management. To know and learn more, it is important to be familiar with various neurological symptoms, disease processes, and sequelae in the acute and chronic phases of COVID-19 infection. Acute neurological illnesses from COVID-19, although uncommon, include acute ischemic strokes, acute neuropathies like Guillian Barre syndrome and acute motor and sensory axonal neuropathy, vasculitis, microhemorrhages, encephalitis, transverse myelitis, and status epilepticus (Khan et al., 2021; Ali et al., 2022; Vaschetto et al., 2020; Garg et al., 2021; Dono et al., 2021). The secondary opportunistic necrotizing infections due to the use of steroids in diabetic coronavirus patients like mucormycosis have significantly skewed the curve to increased mortality (Jain et al., 2022). It is now well known that while the patients presenting with acute critical neurological diseases are few, almost one-third of known cases of COVID-19 infection have mild symptoms in the central and peripheral nervous system. Such neurological symptoms may include headache, dizziness, myalgias, fatigue, anosmia (loss of smell), dysgeusia (loss of taste), cognitive impairment (memory impairment and brain fog), anxiety, and paresthesia (Raveendram et al., 2021). These symptoms may resolve in a few days, but there is also a risk of suffering from these symptoms over a prolonged period of time varying from weeks to months. As mentioned before, such phenomena are now called Long COVID. Some studies have shown that the occurrence of Long COVID can be rather high in adults (Liotta et al., 2020), and it can also occur in children (Thompson, 2021). Interestingly, Long COVID can be seen not only in patients who have been hospitalized in an intensive care unit but also in less serious cases not requiring hospitalization. The association between severity of illness and Long COVID has been found to be insignificant. The risk factors for Long COVID are female sex, age >70 years, and the presence of more than 5 symptoms at onset of initial infection (Crook et al., 2021). The most common symptoms of Long COVID are fatigue and dyspnea. A study done in the UK profiled patients with Long COVID into different clusters, namely a central neurological cluster, a cardiorespiratory cluster, and a systemic/inflammatory cluster (Canas et al., 2022). It was found that the central neurological cluster which was characterized by symptoms such as anosmia, fatigue, brain-fog, depression, delirium, and headache corresponded to the largest cluster in both Alpha and Delta variants, and the second largest for the wild type variant. It was also found that infection by Omicron has a lower risk of developing Long COVID as compared to the Delta variant (Canas et al., 2022).

Neuro Pathophysiology of Long COVID The pathophysiology of COVID-19 infection is very complex but is required to understand the possible etiology of Long COVID. The discussion of

54  Brain and Nervous System

neuropathogenesis in detail is out of the scope of this chapter but we will touch upon and discuss all the important points related to this phenomenon. There are many possible ways that provide virus access to central nervous system. So far studies have shown that SARS-CoV-2 binds to angiotensin convertase enzyme 2 receptors in various locations (Hoffman et al., 2020) and can reach brain tissue via: 1. Nasal mucosa and olfactory bulbs (Klingenstein et al., 2020) 2. Circumventricular organs, midline structures around the third and fourth ventricle (Ong et al., 2022) 3. Direct central nervous system invasion in the setting of viremia (Dey et al., 2021) The entry of the virus occurs from olfactory bulbs, nasal muscosa, circumventricular organs, and by direct invasion in viremia and breakdown of the blood brain barrier. The angiotensin convertase enzyme 2 receptors are expressed in all the above-mentioned areas of the central nervous system. The SARSCoV-2 virus has high affinity for angiotensin convertase enzyme 2 receptors which helps it to gain access to the brain. In addition to binding to angiotensin convertase enzyme 2 receptors, virus entry is also thought to be facilitated via circumventricular organs and the brain. The circumventricular organs are located around the third and fourth ventricles, which lack the blood brain barrier. It is also postulated that the virus can directly invade the central nervous system in the setting of viremia even when the blood brain barrier is intact. We lack a clear understanding of the etiology of Long COVID but to understand it we need to know about the various pathological phenomena that happen during the acute phase of infection. Research has shown that organ damage during acute severe SARS-Cov-2 infection is a result of: 1. 2. 3. 4. 5.

Hyperinflammatory immune response Coagulation abnormalities and thrombosis Endothelial dysfunction Platelet activation Renin-angiotensin axis dysfunction

The hyperinflammatory response is due to the “cytokine storm” resulting in high levels of pro-inflammatory cytokines such as interleukin-6, interleukin1beta, interleukin-18, and granulocyte macrophage colony stimulating factor. Infected human monocytes activate the NOD-, LRR-, and pyrin domaincontaining protein 3 inflammasome which also results in elevated levels of the above interleukins. Inflammatory markers such as ferritin are often elevated in patients with severe COVID-19 (Hu et al., 2021). SARS-CoV-2 infection is a prothrombotic disease. Apart from hypercoagulability, a hypofibrinolytic state is also observed in COVID-19-associated acute respiratory distress syndrome patients. Findings of micro-thrombosis

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in cerebral vessels on autopsy and elevated plasma levels of fibrinogen, von Willbrand Factor, fibrin degradation products, and plasminogen activator inhibitor further support this theory. COVID-19-associated endothelial dysfunction is the most important factor in the pathogenesis. The endothelium is the cell lining of the heart and blood vessels. It is vital in maintaining blood fluidity and regulating blood flow. The chemicals released by the endothelium regulate thrombosis and thrombolysis, platelet and leukocyte interaction with the vessel wall, and the growth of blood vessels. Endothelium dysfunction is a response to acute infection which further triggers the hyperinflammatory and prothrombogenic cascades. This results in further organ damage with short- and long-term adverse consequences. Thus, an intact endothelium is needed to smooth blood flow without thrombogenesis and normal homeostatic balance (Amraei and Rahimi, 2020). Platelet are the key cells involved in physiological thrombosis in an event of vessel wall damage or injury leading to clot formation. In the pathologic state, when platelets are activated, they can lead to vascular thrombosis and occlusion. It is caused by the interaction of activated platelets, the vessel wall, and adhesive proteins like von Willebrand factor and fibrinogen. Platelet activation also triggers the release of procoagulant extracellular vesicles and polyphosphates leading to immunothrombosis (Gu et al., 2021). Renin-angiotensin axis dysfunction is also an important mechanism in COVID-19 pathogenesis. Angiotensin convertase enzyme converts angiotensin II to angiotensin (1-7) which has vasodilator, antiproliferative, and antifibrotic properties. Angiotensin convertase enzyme dysfunction occurs when SARS-CoV-2 binds to it to gain access to various organ systems. It results in endothelial damage causing hyperinflammatory and prothrombotic responses (Lei et al., 2021; Hoffman et al., 2020). All the mechanisms explained above give insight into the pathogenesis during acute COVID-19 infection. However, these acute phenomena are unable to explain the lingering symptoms of COVID-19 in so many patients. We still lack a clear understanding of Long COVID etiopathogenesis, but various researchers have postulated theories to explain the persistence of neurological symptoms weeks and months after the resolution of the acute phase: 1. Hypoxic injury sustained during the acute phase (Solomon et al., 2020) 2. Persistent presence and shedding of viral RNA or proteins in the body triggering the hyperimmune state (Gupta et al., 2020) Among the brain autopsy findings in COVID-19 patients, findings of hypoxic injury, hemorrhage, and inflammation have been noted in the background of chronic neurodegenerative findings (Mukerji and Solomon, 2021; Conklin et al., 2020). Among all findings, brain hemorrhage was the most common abnormality reported, ranging from petechial bleeding and punctate subarachnoid hemorrhages, to large cerebral/cerebellar hemorrhages. Hemorrhagic conversion of middle cerebral artery stroke and subdural hematoma were also

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seen. Large acute and/or subacute infarcts as well as lacunar infarcts/microinfarcts and watershed infarcts were identified in several cases. Cerebral edema with or without herniation was also present in a few cases (Liang et al., 2020) In addition to histopathologic characteristic features correlating with preexisting diseases, including neurodegeneration, chronic/subacute strokes, hepatic encephalopathy, and arteriolosclerosis, there were features of mild to moderate acute hypoxic injury and focal ischemic necrosis (Mukerji and Solomon, 2021). A few studies have found low levels of viral ribonucleic acid in the brain or olfactory nerve, and some rare viral antigen in cranial nerves and brainstem cells. Antibodies to viral nucleocapsid or spike protein were negative while performing immunohistochemistry on the brain, but the olfactory epithelium had a positive response for spike protein (Meinhardt et al., 2021; de Melo et al., 2021; Thakur et al., 2021).

Diagnostic Findings in Acute COVID-19 Patients with Neurological Manifestations Studies have been done to analyze the cerebrospinal fluid profile of COVID19 patients with neurological presentation. Among all common parameters, only cerebrospinal fluid proteins have been seen to be modestly elevated in almost all cases of fatal COVID-19 and in three-quarters of patients with severe and non-severe COVID-19. Cerebrospinal fluid pleocytosis with lymphocytosis was seen in only a few patients. Thus it was concluded that we cannot rely on cell count and polymerase chain reaction for the evaluation of central nervous system invasion of COVID-19 (Tandon et al., 2021). Electroencephalogram abnormalities are common in COVID-19 patients with encephalopathy, seizures, and cardiac arrest. Frontal findings have been seen to be more frequent in COVID-19-associated encephalopathy. Other findings seen on electroencephalogram are diffuse slowing, focal slowing, generalized (or/and lateralized) periodic discharges, and focal/generalized seizures. Only 10–15% patients have epileptiform discharges (Antony and Haneef, 2020). Various studies have been done to evaluate the pattern of injury on magnetic resonance imaging brain scans in patients with COVID-19. It has been found that microscopic hemorrhagic and ischemic lesions are found in the corpus callosum, subcortical, and deep white matter. This distribution is similar to that seen in patients with hypoxic respiratory failure, sepsis, and disseminated intravascular coagulation (Conklin et al., 2020; Conklin et al., 2021). In some patients with anosmia, transient signal abnormalities in olfactory bulbs can be seen. Brain positron emission tomography scans of patients with Long COVID were compared to those of heathy subjects in one study. Brain hypometabolism in patients of Long COVID involving the olfactory gyrus and connected limbic/paralimbic regions extended to the brainstem and the cerebellum. It

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was found that areas in which hypometabolism was present were related to the symptoms of patients (Guedj et al., 2021).

Symptoms and Their Management The varied symptomatology of Long CVOID represents a substantial health care burden because of the loss of working hours, effect on mental health, and decreased functionality of the affected individual. Strangely, a young patient with COVID may die while an elderly man may remain asymptomatic and recover. There are no particular diagnostic investigations to rule in or rule out postCOVID syndrome; therefore, Long COVID is a diagnosis of exclusion which can only be made once common disease processes for the symptoms are ruled out. Various differential diagnoses to be considered in patients presenting with neuropsychiatric symptomatology are stroke, cerebral venous sinus thrombosis, seizure, peripheral neuropathies, and neurodegenerative diseases. Patients should be screened for anxiety, depression, and post-traumatic disorder. Studies have shown that there are no significant findings in routine laboratory and rheumatologic tests, inflammatory or immunologic markers, pulmonary function tests, echocardiography, neurocognitive testing, or serologic tests for SARS-CoV-2. Still, routine lab tests like complete blood count, basic metabolic panel, hepatic function tests, hemoglobin A1C, thyroid function test, thiamine, folate, and vitamin B12 should be evaluated to rule out mimicking diseases. Electroencephalography and electromyography should be considered if there are concerns about seizures or paresthesias respectively. It is estimated that about 30% of non-hospitalized and 80% of hospitalized COVID-19 patients experienced one or more symptoms of Long COVID (Taquet et al., 2021; Davis et al., 2021). Patients with Long COVID can experience relapsing-remitting symptoms like COVID-19 itself, which affects all organ systems. The various neuropsychiatric symptoms noted during Long COVID are: 1. Fatigue 2. Headache 3. Post-exertional malaise 4. Irritability 5. Brain fog (cognitive dysfunction) 6. Impaired concentration 7. Memory problems 8. Difficulty in finding words 9. Postural orthostatic tachycardia syndrome 10. Anxiety and depression With therapeutic interventions to target COVID-19 and the development of vaccines for prophylaxis, the research on the exploration and management of Long COVID is gaining momentum.

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Common long-term effects associated with COVID-19 and their management:

Headache Headache has been found to be an early onset symptom of COVID-19 and can emerge as an isolated symptom. It is a common symptom, like in any acute viral illness, not localizing to any particular location in the central nervous system. But unlike the headache associated with common viral infections, it may persist in COVID-19 patients even after recovery. The prevalence of headaches during the acute phase is around 10% whereas in post-COVID syndrome it is 2–15%. The features of headache in COVID-19 are like those of tension headache or typical migraine having a persistent and throbbing quality. It was observed that patients with a history of migraine who had headache at the onset of COVID-19 were more likely to have headache as a long-term post-COVID symptom. However, headaches in Long COVID can occur in patients with no prior history of chronic headache disorder, thereby implying that chronic headaches could just be the outcome of infection itself (Penas et al., 2021; Marteletti et al., 2021). The exact pathogenesis of COVID-19-related headaches is unclear, but the role of cytokine storm during COVID-19 has been hypothesized. The reason is that tension and migraine headaches have an established association with the activation of mast cells, elevated levels of IL-6, and angiotensin convertase enzyme. Hyperexcitability of the trigemino-vascular system could also be one of the possible mechanisms for headache in COVID-19 (Caronna and Pozo-Rosich, 2021). Headaches can be a very debilitating symptoms for COVID-19 patients. They can clear up after 2 months while in some patients they can persist for 3–6 months. The best preventative action against post-COVID headaches is the COVID-19 vaccine. In general, when patients present with migraine-like headache post-COVID, a trial of migraine therapies is recommended. So far, there are no specific treatments for headaches associated with COVID-19.

Anosmia and Dysgeusia Anosmia and dysgeusia are some of the most common reported symptoms at the onset of COVID-19 and can occur in the absence of nasal congestion. The prevalence is reported in around 80% of patients. The resolution of these symptoms varies between 8 and 37 days in different studies, but in some cases the resolution of these symptoms can take 4–8 months (Andrews et al., 2020). Smell and olfactory training is recommended for anosmia. Olfactory training is an exercise constituting sniffing four different strong smells daily at least for 10 seconds in order to stimulate olfactory neurons and enhance recovery (Kollndorfer et al., 2014). Medical therapy like steroids is added adjunctively if there is associated edema in nasal or paranasal sinuses.

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Dysgeusia is the disorder in which the sense of taste is impaired. It is a relatively challenging condition to treat. Usually it is recommended to treat the condition which is thought to be the etiology of dysgeusia, e.g. to treat gastroesophageal reflux if it is thought to be the primary etiology. However, most of the time, the etiology is either not known or does not have a clear treatment. In such cases, trial use of clonazepam has been suggested by some anecdotal data which supports the use of clonazepam in cancer-related dysgeusia (Epstein et al., 2019).

Fatigue Fatigue is one of the most common sequelae of acute COVID-19. This impairment is also described as post-infectious fatigue syndrome and post-viral fatigue syndrome. It is reported to be unrelieved by sleep or rest and is out of proportion to illness. It may last for days, months, or even longer without returning to baseline. Patients reportedly suffer from “brain fog” – neurocognitive impairment – as well. Treatment is focused on symptomatic therapies to enhance functional capacity. Some individuals experience both fatigue as well as other symptoms such as post-exertional malaise, unrefreshing sleep, and cognitive impairment, and these individuals can meet criteria for myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS). Some studies indicate that over 40% of Long COVID patients will be categorized as having ME/CFS ( Bonilla et al., 2022; Haffke et al., 2022; Jason & Islam, 2022; Kedor et al., 2022; Mancini et al., 2021).

Cognitive Dysfunction As mentioned earlier, cognitive impairment is reported by patients as “brain fog.” They have difficulty in concentrating and finding words. Memory may be affected sometimes. There are studies showing the worsening of many mental scores post-COVID and problems with immediate memory and attention. Impairment in processing speed and executive function have been reported also. These deficits were also noted in hospitalized as well as non-hospitalized patients with mild disease. Prolonged duration of intensive care unit stay contributes significantly to long-term cognitive impairment in COVID-19 patients (Mattioli et al., 2022; Ollila et al., 2022). The onset of neuro-degenerative dementias may be accelerated leading to long-term cognitive decline in COVID-19. The probability of experiencing memory symptoms increases in the first few months. These symptoms are equally common across all ages and have substantial effects on daily life. They affect quality of work, decision making skills, communication, conversations, driving, remembering medications, following simple instructions, and day-to-day activities (Frontera et al., 2021; Vannorsdall et al., 2022). Improvement in cognition is seen with time in most cases though some deficits may persist in a few cases. Objective cognitive assessment is needed

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to evaluate the degree and type of cognitive impairment. Patients need psychological support and motivational support to participate in a regimented cognitive rehabilitation. Multidisciplinary care involving primary care specialties including neurology and physical rehab medicine has shown better results. Patients should be evaluated for dysautonomia and post-traumatic stress disorder as these can lead to brain fog and are treatable causes. Exercise programs focusing on resistance, endurance, and balance training have been shown to improve cognition. Cardiovascular exercises have also been shown to improve attention, processing speed, executive functioning, and memory. These exercises may be implemented in person or through tele-rehab consultations (Chang et al., 2012; Gregory et al., 2011; Li et al., 2022).

Sleep Disorders Problems with insomnia, frequent awakenings, inability to breathe, restless legs, vivid dreams, and nightmares are encountered in COVID patients. Although some of the patients had pre-existing sleep disturbances, per data the prevalence has certainly increased after COVID-19. A high frequency of sleep disorders (approximately 75%) was expected in COVID-19 patients since the core symptoms of the disease involve coughing and difficulty breathing, all of which have been associated with sleep disorders. Physical pain and side effects of antiviral medications also contribute to the higher risk of sleep problems. One might argue that the higher prevalence rates of sleep problems among COVID-19 patients are a by-product of a smaller study sample size. Yet, it is important to give it serious thought until a longer and a better study design is available. Women, home-bound patients, and non-working patients are likely to have impaired sleep quality. It is recommended such patients should have in-person or telehealth evaluation by a sleep specialist to assess if positive airway pressure ventilation can help them. Patients should be educated about sleep hygiene and should be treated medically for their insomnias. Depression and anxiety also affect sleep adversely so patients should be screened for them too. Peer education could significantly reduce the anxiety and depression, thereby improving sleep quality and mental health (Pinto et al., 2020).

Anxiety and Depression Psychiatric distress with anxiety and depression are very common in Long COVID. This is associated with functional decline and is seen in almost onethird of COVID-19 survivors. The prevalence of post-traumatic stress disorder, anxiety, and depression is the same in patients who were hospitalized as compared to non-hospitalized COVID-19 patients. In addition, the COVID19 pandemic has upended normal life around the world from economic disturbance to social isolation. These indirect factors also contribute to mental health implications. Data demonstrates an increased risk of a psychiatric diagnosis within 90 days of a patient receiving a positive test result when compared to

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other medical illnesses. Post-traumatic stress disorder symptoms often include frequent rumination on the illness, insomnia, and emotional lability, which most often are likely to be seen in the post-illness stage (Mazza et al., 2020; Halpin et al., 2021). Complete neuropsychological evaluation should be done to recognize the disorder. Based on that, recommendations should be made for psycho-education, psychotherapy, psychopharmacology, and peer support. On an in-patient basis, it has been recommended that occupational therapists, social workers, and psychologists should provide psychological support and intervention. A plan for discharge should also include follow-up with psychological services. Patients can benefit from tele-therapy or tele-counseling to address emotional and mood disturbances, and initial studies have demonstrated improvement with this intervention. Moreover, some patients may have reservations about in-person visits, particularly those with symptoms of post-traumatic stress disorder, and may be more likely to engage in treatment if remote treatment is made available (Aiyebusi et al., 2021).

Postural Orthostatic Tachycardia Syndrome Postural orthostatic tachycardia syndrome is a syndrome in which patients experience tachycardia and symptoms of orthostatic intolerance within 10 minutes of assuming upright posture, and in the absence of orthostatic hypotension. In adults the heart rate must increase by at least 30 bpm within 10 minutes, and by at least 40 bpm in adolescents ( Raj et al., 2021). It is one of the sequalae of COVID-19 survivors who present with palpitations or tachycardia. The management of Postural Orthostatic Tachycardia Syndrome is discussed in detail in the chapter on autonomic dysfunction. Briefly, it relies on the use of different strategies with an aim to reduce the symptoms and distress caused by it. Exercises and physical activity along with slow transition while changing posture are helpful. Keeping oneself hydrated and increasing the daily salt intake may also help. There is some evidence supporting the use of compression stockings. Among therapeutic interventions, medications like fludrocortisone, pyridostigmine, midodrine, and beta blockers may aid in reducing the symptoms. Ivabradine is a Food and Drug Administration-approved medication that selectively inhibits the sino-atrial node to reduce heart rate, and may be effective in relieving the symptoms in postural orthostatic tachycardia syndrome.

Conclusion Overall, close follow-up of all COVID-19 patients during the recovery phase requires a team approach to identify the cases of Long COVID with neuropsychiatric problems. A holistic and inter-professional team approach with close communication between the primary care physicians, neurologists, and behavioral health experts should provide better results. Such coordinated care will not only enhance the patient care but will reduce hospital

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admissions and the exhaustion of health care resources in this pandemic. Proper patient education regarding self-monitoring at home, follow-up by a home health aide, if possible, encouragement to seek emergency care when needed, consultation with a behavioral health counselor, mental and physical health exercise training, vaccination for COVID-19, and involvement with support groups would benefit patients of Long COVID irrespective of their symptomatology. We must try to prevent the occurrence of Long COVID in addition to managing the symptoms. There is moderate evidence showing the benefit of vaccination in lowering the risk of long-term COVID symptoms (Azzolini et al., 2022). Unvaccinated people getting COVID-19 infection are more likely to have serious symptoms for longer than 4 weeks. The prognosis of this new clinical entity is not known yet. However, the prognosis depends upon the severity of the clinical neurological symptoms, underlying comorbid conditions, and response to the treatment. Larger studies are needed to evaluate short- and long-term prognosis in Long COVID.

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Brain and Nervous System  65 Haffke M, Freitag H, Rudolf G, et al. (2022). Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). Journal of Translational Medicine, 20(138). https://doi​.org​/10​.1186​/s12967​ -022​-03346​-2. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N. H., Nitsche, A., Müller, M. A., Drosten, C., & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271–280.e8. https://doi​ .org​/10​.1016​/j​.cell​.2020​.02​.052 Hu, B., Huang, S., & Yin, L. (2021). The cytokine storm and COVID-19. Journal of Medical Virology, 93(1), 250–256. https://doi​.org​/10​.1002​/jmv​.26232 Jain, V., Senetar, A. J., Maciel, C. B., Remley, W., Islam, S., Fredenburg, K. M., Babi, M. A. and Robinson, C. P. (2022). A 40-year-old woman with COVID-19 and bilateral vision loss. The Neurohospitalist, 19418744221114209. Jason, L. A., & Islam, M. F. (2022). A classification system for Post-Acute Sequelae of SARS CoV-2 Infection. Central Asian Journal of Medical Hypotheses and Ethics, 3(1), 38– 51. https://cajmhe​.com​/index​.php​/journal​/article​/view​/146​/66 Kedor, C., Freitag,H., Meyer-Arndt, L., Wittke, K., Hanitsch, L. G., Zoller, T., Scheibenbogen, C. (2022). A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nature Community, 13(1), 5104. https://doi​.org​/10​ .1038​/s41467​-022​-32507​-6. Khan, F., Sharma, P., Pandey, S., Sharma, D. V. V., Kumar, N., Shukla, S., Dandu, H., Jain, A., Garg, R. K., & Malhotra, H. S. (2021). COVID-19-associated Guillain-Barre syndrome: Postinfectious alone or neuroinvasive too? Journal of Medical Virology, 93(10), 6045–6049. https://doi​.org​/10​.1002​/jmv​.27159 Klingenstein, M., Klingenstein, S., Neckel, P. H., Mack, A. F., Wagner, A. P., Kleger, A., Liebau, S., & Milazzo, A. (2020). Evidence of SARS-CoV2 entry protein ACE2 in the human nose and olfactory bulb. Cells, Tissues, Organs, 209(4–6), 155–164. https://doi​ .org​/10​.1159​/000513040 Kollndorfer, K., Kowalczyk, K., Hoche, E., Mueller, C. A., Pollak, M., Trattnig, S., & Schöpf, V. (2014). Recovery of olfactory function induces neuroplasticity effects in patients with smell loss. Neural Plasticity, 2014, 140419. https://doi​.org​/10​.1155​/2014​ /140419 Lei, Y., Zhang, J., Schiavon, C. R., He, M., Chen, L., Shen, H., Zhang, Y., Yin, Q., Cho, Y., Andrade, L., Shadel, G. S., Hepokoski, M., Lei, T., Wang, H., Zhang, J., Yuan, J. X., Malhotra, A., Manor, U., Wang, S., Yuan, Z. Y., … Shyy, J. Y. (2021). SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circulation Research, 128(9), 1323–1326. https://doi​.org​/10​.1161​/CIRCRESAHA​.121​ .318902 Li, J., Xia, W., Zhan, C., Liu, S., Yin, Z., Wang, J., Chong, Y., Zheng, C., Fang, X., Cheng, W., & Reinhardt, J. D. (2022). A telerehabilitation programme in post-discharge COVID-19 patients (TERECO): A randomised controlled trial. Thorax, 77(7), 697– 706. https://doi​.org​/10​.1136​/thoraxjnl​-2021​-217382 Liang, J. W., Reynolds, A. S., Reilly, K., Lay, C., Kellner, C. P., Shigematsu, T., Gilligan, J., Majidi, S., Al-Mufti, F., Bederson, J. B., Mocco, J., Dhamoon, M. S., Dangayach, N. S., & Mount Sinai Stroke Investigators (2020). COVID-19 and Decompressive Hemicraniectomy for Acute Ischemic Stroke. Stroke, 51(9), e215–e218. https://doi​.org​ /10​.1161​/STROKEAHA​.120​.030804

66  Brain and Nervous System Liotta, E. M., Batra, A., Clark, J. R., Shlobin, N. A., Hoffman, S. C., Orban, Z. S., & Koralnik, I. J. (2020). Frequent neurologic manifestations and encephalopathyassociated morbidity in Covid-19 patients. Annals of Clinical and Translational Neurology, 7(11), 2221–2230. https://doi​.org​/10​.1002​/acn3​.51210 Mancini DM, Brunjes DL, Lala A, Trivieri MG, Contreras JP, Natelson BH. (2021). Use of cardiopulmonary stress testing for patients with unexplained dyspnea post-coronavirus disease. JACC Heart Failure, 9(12), 927–37. Martelletti, P., Bentivegna, E., Spuntarelli, V., & Luciani, M. (2021). Long-COVID headache. SN Comprehensive Clinical Medicine, 3(8), 1704–1706. https://doi​.org​/10​.1007​ /s42399​-021​-00964-7 Mattioli, F., Piva, S., Stampatori, C., Righetti, F., Mega, I., Peli, E., Sala, E., Tomasi, C., Indelicato, A. M., Latronico, N., & De Palma, G. (2022). Neurologic and cognitive sequelae after SARS-CoV2 infection: Different impairment for ICU patients. Journal of the Neurological Sciences, 432, 120061. https://doi​.org​/10​.1016​/j​.jns​.2021​.120061 Mazza, M. G., De Lorenzo, R., Conte, C., Poletti, S., Vai, B., Bollettini, I., Melloni, E., Furlan, R., Ciceri, F., Rovere-Querini, P., COVID-19 BioB Outpatient Clinic Study Group, & Benedetti, F. (2020). Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain, Behavior, and Immunity, 89, 594–600. https://doi​.org​/10​.1016​/j​.bbi​.2020​.07​.037 Meinhardt, J., Radke, J., Dittmayer, C., Franz, J., Thomas, C., Mothes, R., Laue, M., Schneider, J., Brünink, S., Greuel, S., Lehmann, M., Hassan, O., Aschman, T., Schumann, E., Chua, R. L., Conrad, C., Eils, R., Stenzel, W., Windgassen, M., Rößler, L., … Heppner, F. L. (2021). Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nature Neuroscience, 24(2), 168–175. https://doi​.org​/10​.1038​/s41593​-020​-00758-5 Mukerji, S. S., & Solomon, I. H. (2021). What can we learn from brain autopsies in COVID-19?. Neuroscience Letters, 742, 135528. https://doi​.org​/10​.1016​/j​.neulet​.2020​ .135528 Ollila, H., Pihlaja, R., Koskinen, S., Tuulio-Henriksson, A., Salmela, V., Tiainen, M., Hokkanen, L., & Hästbacka, J. (2022). Long-term cognitive functioning is impaired in ICU-treated COVID-19 patients: A comprehensive controlled neuropsychological study. Critical Care, 26(1), 223. https://doi​.org​/10​.1186​/s13054​-022​-04092-z Ong, W. Y., Satish, R. L., & Herr, D. R. (2022). ACE2, circumventricular organs and the hypothalamus, and COVID-19. Neuromolecular Medicine, 1–11. Advance online publication. https://doi​.org​/10​.1007​/s12017​-022​-08706-1 Pinto, J., van Zeller, M., Amorim, P., Pimentel, A., Dantas, P., Eusébio, E., Neves, A., Pipa, J., Santa Clara, E., Santiago, T., Viana, P., & Drummond, M. (2020). Sleep quality in times of Covid-19 pandemic. Sleep Medicine, 74, 81–85. https://doi​.org​/10​.1016​/j​ .sleep​.2020​.07​.012 Raj, S. R., Arnold, A. C., Barboi, A., Claydon, V. E., Limberg, J. K., Lucci, V. M., Numan, M., Peltier, A., Snapper, H., Vernino, S., & American Autonomic Society (2021). Long-COVID postural tachycardia syndrome: An American autonomic society statement. Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society, 31(3), 365–368. https://doi​.org​/10​.1007​/s10286​-021​-00798-2 Raveendran, A. V., Jayadevan, R., & Sashidharan, S. (2021). Long COVID: An overview. Diabetes & Metabolic Syndrome, 15(3), 869–875. https://doi​.org​/10​.1016​/j​.dsx​.2021​.04​ .007 Sampson, A. T., Heeney, J., Cantoni, D., Ferrari, M., Sans, M. S., George, C., Di Genova, C., Mayora Neto, M., Einhauser, S., Asbach, B., Wagner, R., Baxendale,

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5

Respiratory System Tanya E. Melnik, MD, MS, Hem Desai, MBBS MPH, Sarah Zach, BM, MS, CCC-SLP, and Stephanie Misono, MD MPH

Respiratory symptoms, such as shortness of breath and cough, are frequently reported by COVID-19 survivors regardless of the severity of illness (Fernández-de-Las-Peñas et al., 2022; Fjelltveit et al., 2022) and are associated with decreased quality of life, impaired functional capacity, and increased healthcare utilization (Malik et al., 2022; Cortés-Telles et al., 2021). The evaluation and management of patients with respiratory sequelae of COVID19 may be challenging as the pathophysiology of dyspnea and cough are not completely understood, and interventions are still being evaluated for effectiveness. Nonetheless, accumulated evidence and experience with other respiratory conditions inform approaches to common respiratory complaints. In this chapter, we discuss respiratory manifestations in both the lower and upper airways. The lower airway portion is divided into reviews of the sequelae of both mild and severe disease.

Lower Airway Respiratory Manifestations of Long COVID: Case Report of Respiratory Sequelae: Mild COVID-19 A 40-year-old previously healthy male presented to a virtual post-COVID clinic with dyspnea on exertion, tachycardia, and fatigue 3 months following acute COVID-19 illness. Acute symptoms had included sore throat, body aches, low-grade fever, and chills. Cough and shortness of breath prompted evaluation in the emergency room where he was diagnosed with pneumonia based on chest X-ray findings of subtle ground-glass infiltrates in the left midlung and right medial lung base. Budesonide inhaler and supportive care were recommended. In the following 3 months his dyspnea had only partially improved. Acute COVID-19 often starts with respiratory symptoms, such as cough, sore throat, rhinorrhea, dyspnea, and fever (Huang et al., 2020). Lungs are often involved even in patients with mild infection as evidenced by radiographic findings of viral pneumonia (Liu et al., 2020b). Pulmonary thromboembolism can also occur, particularly in moderate or severe disease (Torres-Castro et DOI: 10.4324/9781003371090-5

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al., 2021; Xie et al., 2022a). Both acute processes can lead to core respiratory features of Long COVID: cough and dyspnea. The pathophysiology of Long COVID respiratory symptoms remains incompletely understood and likely multifactorial. Over 40% of hospitalized patients have persistent changes, such as ground-glass opacities, mixed ground-glass and subpleural parenchymal bands, and pure parenchymal bands on chest CT 3 months after discharge (Liu et al., 2020a; Tabatabaei et al., 2020). Fibrotic changes were observed more frequently in patients with severe disease, possibly due to infection-related tissue damage and mechanical ventilation barotrauma (van Gassel et al., 2021). Ventilation abnormalities, likely due to small airway involvement, have been observed both in MRI studies and impulse oscillometry even in patients with normal DLCO on pulmonary function testing and normal chest CT (Lopes et al., 2021; Inui et al., 2022; Kooner et al., 2022). Perfusion abnormalities have been identified in follow-up studies of ambulatory and previously hospitalized patients with Long COVID (Nagpal et al., 2021, Matheson et al., 2022). The pathophysiology of these changes is likely multifactorial with vasoconstriction, vascular remodeling, and microemboli contributing to some degree (Lins et al., 2020). Pulmonary function testing in COVID-19 survivors has demonstrated a range of abnormalities, from restrictive to obstructive patterns and decreased DLCO (Cortés-Telles et al., 2021). Meta-analysis of published studies found a prevalence of 39% for altered DLCO, 15% for restrictive pattern, and 7% for obstructive pattern seen on pulmonary function test (Torres-Castro et al., 2021). The approach to the patient with lingering respiratory symptoms following COVID-19 is driven both by the pathophysiology of acute disease and recovery, and by the impact of pre-existing health issues (Philip et al., 2022). Therefore, careful history of both acute illness, including presenting symptoms and their evolution, disease severity, and treatment, as well as preexisting medical conditions and functional limitations become important. Given the lack of a pathognomonic clinical presentation for Long COVID, symptoms emerging during recovery from acute illness should not be automatically attributed to COVID-19 sequelae, and initial differential diagnoses should be broad. Several guidelines on the evaluation and management of post-COVID respiratory symptoms have been published (e.g., Shah et al., 2021). Symptoms, including their onset and duration in relationship to initial COVID-19 illness, such as dyspnea, cough, palpitations, paroxysmal nocturnal dyspnea, lower extremity edema, and heartburn, rhinorrhea, and nasal congestion, can help to narrow differential diagnosis. Complete review of symptoms should be performed as Long COVID is often not limited to respiratory symptoms alone. Physical examination of the patient with respiratory complaints should include vital signs (respiratory rate, pulse, oxygen saturation, blood pressure, and orthostatic changes) as well as heart, lung, and upper airway examination. The clinical picture guides further cardiopulmonary testing and referrals (see Figure 5.1). The optimal timing and choice of chest imaging for patients with respiratory symptoms has not been definitively determined, but it is prudent to obtain

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Figure 5.1  Flowchart of potential diagnostic workup for patients with persistent respiratory symptoms following COVID-19, with a particular focus on interstitial infiltrate.

follow-up imaging in patients with prior documented abnormalities during acute illness to assure the resolution of parenchymal changes. In the absence of worsening or new symptoms, imaging can be performed at 12 weeks after acute COVID-19. Chest CT can be considered the imaging of choice for patients with prior abnormal imaging. Chest X-ray can be performed in patients without prior imaging or with normal baseline studies. Additional imaging and pulmonary medicine consultation may be warranted in patients with persistent radiographic findings. Cardiac evaluation, such as transthoracic echocardiogram, may be warranted in patients with signs and symptoms suggestive of

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cardiac causes of dyspnea. New cardiovascular diagnoses were identified in 23% of patients with Long COVID referred to cardiology in one study (Wang et al., 2022). Pulmonary function testing (PFT) remains paramount in patients with persistent respiratory symptoms, and can distinguish between obstructive and restrictive disease as well as fixed and dynamic obstruction. Patients with abnormalities on initial testing should be followed longitudinally, particularly after severe disease given the increased prevalence of PFT changes in this group (Froidure et al., 2021). Exercise capacity and oxygenation may also be evaluated in patients with persistent dyspnea, particularly in patients with reduced exercise tolerance (Cortés-Telles et al., 2021). We continue our discussion of the mild COVID-19 case report below. Evaluation prior to referral to post-COVID clinic included a physical exam and chest computed tomography which was negative for pulmonary embolism and parenchymal lung pathology. Cardiac MRI did not identify myocardial or pericardial disease. Pulmonary function tests demonstrated reduced inspiratory flow rates, but were otherwise normal. The patient was evaluated by otolaryngology, and flexible fiberoptic laryngoscopy was normal. Referral to speech therapy was made. Impaired respiratory mechanics were identified; breathing exercises were recommended. Medical management of dyspnea in patients with respiratory symptoms of Long COVID is aimed at addressing underlying pathophysiology, including any preexisting medical conditions. While systemic corticosteroids have demonstrated some efficacy for patients with abnormal imaging in small clinical trials, they are best reserved for patients with organizing pneumonia (Goel et al., 2021). Bronchodilator responsiveness and functional improvement have been seen in patients with a history of moderate and severe disease (Maniscalco et al., 2021a; Maniscalco et al., 2021b). Given small airway disease findings, a trial of inhaled corticosteroids could be considered, particularly in patients with obstructive pattern on pulmonary function testing. Other therapeutic agents, such as leukotriene inhibitors, are currently in clinical studies. Patients should be encouraged to participate in ongoing clinical studies aimed at the identification of underlying pathophysiology as well as effective treatment modalities. Currently the therapeutic armamentarium for dyspnea following COVID-19 and minimal parenchymal lung involvement is very limited. Pulmonary rehabilitation has emerged as an effective intervention for dyspnea in patients with Long COVID regardless of the disease severity. Improvements in 6-minute walk, dyspnea, and overall functional status were seen in both ambulatory and previously hospitalized patients with COVID-19 (Nopp et al., 2022; Spielmanns et al., 2021). Several studies have identified possible factors explaining benefits of pulmonary rehabilitation for persistent dyspnea following COVID-19. Cardiopulmonary exercise testing identified sarcopenia and muscle dysfunction as contributing causes of persistent dyspnea in Long COVID (Gobbi et al., 2021; Mohr et al., 2021; Hennings et al., 2022). Breathing dysregulation has also been proposed as a contributor to dyspnea and poor exercise

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tolerance (Beaudry et al., 2022; Stebneis et al., 2022). No consistent pattern of dysfunctional breathing has been observed in the studies, however, hyperventilation was not prevalent (Frésard et al., 2022; von Gruenewaldt et al., 2022). This can complicate clinical diagnosis of dysfunctional breathing in patients with Long COVID, but the use of breathing assessment tools can improve diagnostic accuracy (Hylton et al., 2022). Some dyspneic patients with Long COVID meet criteria for diagnosis of myalgic encephalitis/chronic fatigue syndrome (ME/CFS) (Mancini et al., 2021). Post-exertional malaise and dyspnea are common complaints in ME/CFS with incompletely understood underlying pathophysiology. Factors such as altered somatic perception and autonomic dysfunction, are thought to be contributors in some patients with ME/ CFS (Ravindran et al., 2012). It is not clear if the mechanism of dyspnea in Long COVID is similar to dyspnea seen in ME/CFS. However, given postexertional malaise encountered by patients with Long COVID with features of chronic fatigue syndrome, exercise-based rehabilitation programs need to be tailored to the needs of these patients (Herrera et al., 2021).

Case Report of Respiratory Sequelae: Severe COVID-19 A 57-year-old male with a history of hypertension and diabetes presented to the emergency room with hypoxemic respiratory failure. He was intubated in the ER and admitted to the medical ICU for further care. He was PCRpositive for SARS-CoV-2 infection. His CT chest showed bilateral ground glass opacities (Figure 5.2a). He was treated with a standard regimen, including remdesivir, corticosteroids, and tocilizumab. He required high ventilatory support and pronation therapy. He slowly improved over the next 7 days and was extubated to 4 LPM nasal oxygen. He passed a swallow evaluation and was able to tolerate oral intake. Two days later, the patient developed worsening hypoxemia and dyspnea. He was reintubated after failing noninvasive ventilatory therapy. His CT chest

Figure 5.2  Progression and resolution of organizing pneumonia. 2a: bilateral ground glass infiltrates are noted on presentation. 2b: Peribronchovascular nodules and peripheral nodular density suggestive of organizing pneumonia. 2c :Significant improvement following 1 week of corticosteroid treatment.

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now showed peribronchovascular and subpleural nodules. Bronchoalveolar lavage suggested lymphocytic alveolitis. Extensive infectious workup was negative. Echocardiogram was normal. Based on CT imaging and negative infectious workup, a provisional diagnosis of organizing pneumonia (OP) was made. Treatment included high dose IV corticosteroid therapy (500 mg methylprednisolone for 48 hours) followed by 1 mg/kg prednisone. He achieved extubation in 3 days. CT chest 1 week later showed improvement in lung parenchyma (Figure 5.2b). He was switched to oral 1 mg/kg prednisone and followed in an outpatient clinic with resolution of lung infiltrates (see Figure 5.2c). Prednisone was tapered off slowly over 4 months without recurrence. While acute lung injury is the primary feature of SARS-Cov-2 viral infection, understanding further implications is critical (Osuchowski et al., 2021; Bösmüller et al., 2021). Given the large number of infected patients, even relatively rare sequelae can affect many patients and create a significant healthcare burden. The incidence of severe organizing pneumonia following COVID-19 is 3–5% in the United States (Vadász et al., 2021). This patient has had a post-COVID-19 organizing pneumonia (OP). OP is a distinct clinicopathological entity that may occur as a pulmonary reaction to various injuries, with viral infection among the most common etiology (Torrego et al., 2010). Organizing pneumonia has been associated with prior viral outbreaks of swine flu and seasonal influenza as well as H1N1 pandemic influenza (Zanetti et al., 2013). Radiological findings typically include peripheral consolidation, ground-glass infiltrates, and/or solitary nodules. “Atoll sign” which is a ring showing opacity surrounding ground glass opacities has been described in OP (Kim et al., 2003). Biopsy is the gold standard for diagnosis, but may be difficult to obtain, especially in severely ill patients with high oxygen requirements. Bronchoalveolar lavage showing lymphocytic alveolitis with mixed cellular pattern with radiological findings and high index of suspicion is needed to diagnose OP (Alasaly et al., 1995). OP responds very well to corticosteroids and requires a taper of prednisone over 3–4 months (Drakopanagiotakis et al., 2008). Some patients may experience a relapse of OP after tapering corticosteroids and can benefit from steroid-sparing agents such as cyclophosphamide, mycophenolate, and azathioprine (Epler, 2011). Other sequelae of COVID-19 leading to persistent hypoxia include interstitial lung disease (ILD) flare and pulmonary fibrosis. Patients with underlying interstitial lung disease are at increased risk of developing severe COVID19 infection due to their immunosuppressed state and underlying structural lung abnormalities (Huang et al., 2020). Flares of hypersensitivity pneumonitis and rheumatoid arthritis-associated ILD following COVID-19 infection have been reported (Fonseca et al., 2021). However, mechanisms triggered during an exacerbation remain poorly elucidated (Wootton et al., 2011). ILD exacerbation in COVID-19 infection presents a diagnostic dilemma as common diagnostic features of ILD exacerbation such as the worsening of lung infiltrates and respiratory symptoms can be seen in COVID-19 infection as well. Patients with ILD presenting with acute COVID-19 should be treated with

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appropriate antiviral therapy. If symptoms fail to improve, and persistent interstitial infiltrates suggestive of ILD exacerbation are seen, immunosuppressive therapy should be considered. Multidisciplinary discussion with a pulmonologist, radiologist, and rheumatologist will be helpful to correctly distinguish ILD exacerbation from COVID-19 infection (Fonseca et al., 2021). Pulmonary fibrosis affects over 20% of COVID-19 survivors (Grant et al., 2020). The molecular basis for progression to pulmonary fibrosis is unknown and may be multifactorial, resulting from cytokine storm, direct viral damage, and upregulation of fibrosis through ACE2 signaling pathway, which can be explained by the upregulation of TGF-β (​​Wigén et al., 2020). The use of antifibrotics such as pirfenidone and nintedanib has been suggested to treat COVID-associated pulmonary fibrosis. These antifibrotics have been well studied in the treatment of idiopathic pulmonary fibrosis which is also characterized by the over-expression of TGF-β (King et al., 2014). A study by Zhang et al. did not show any significant improvement in pulmonary fibrosis in severe COVID-19 patients. However, it confirmed the benefits of pirfenidone therapy in anti-inflammatory responses (Zhang et al., 2022). Several clinical trials are currently in progress to assess the effect of pirfenidone as well as nintedanib in post-COVID pulmonary fibrosis. Antifibrotic agents may be considered in patients with declining PFTs even after recovery from initial COVID-19 infection and clear evidence of pulmonary fibrosis on chest imaging. Pulmonary hypertension has been a concern for COVID-19 survivors due to the increased risk of pulmonary thromboembolism in acute illness. However, there has not been a corresponding increase in the reported incidence of chronic thromboembolic pulmonary hypertension following COVID-19 outbreak (Newman et al., 2021). Significant pulmonary fibrosis following COVID-19 infection can also cause pulmonary hypertension due to the severity of underlying lung disease (Patel et al., 2007). Inhaled treprostinil has shown efficacy in treating pulmonary hypertension due to interstitial disease and also has shown to slow the progress of pulmonary disease (Waxman et al., 2021). Inhaled treprostinil should be considered in patients with a degree of pulmonary hypertension out of proportion to the severity of pulmonary fibrosis. Lung transplant can be lifesaving in end-stage lung disease. The high cost, the need for robust lung transplant programs, and the availability of donor lungs are some of the challenges faced. Patients with worsening post-COVID interstitial lung disease despite maximal therapy should be referred to lung transplantation.

Upper Airway Respiratory Manifestations of Long COVID In addition to lower respiratory manifestations of post-COVID, the upper airway can be affected as well. Potential findings include upper airway cough, airway stenosis, dysphagia, and dysphonia. The precise incidence of upper airway-related challenges is unknown, but in an EHR study of over 273,000 careseeking patients with a history of COVID-19, over one-third had persistent

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symptoms beyond 3 months, including abnormal breathing (8%) and chest/ throat pain (6%) (Tacquet et al., 2021). A meta-analysis representing over 10,000 patients also noted that dyspnea (21%) and cough (11%) were among the most common symptoms reported by adults with persistent post-COVID symptoms (Healey et al., 2022). Cough may be associated both with pulmonary abnormalities, as above, and laryngeal hypersensitivity (Kang et al., 2022). Triggers for cough may include stimuli such as talking, singing, laughing, physical activity, air temperature changes, smoke, fumes, stress, post-nasal drip, and reflux (Morrison et al., 1999). Paradoxical vocal fold motion or dynamic airway obstruction can also occur (Lechien et al., 2021; El Kik et al., 2022). Complications of intubation include airway stenosis of the subglottis and/or mid trachea (Stratakos et al., 2022; Piazza et al., 2022). In a subset, additional problems such as airway fracture and distortion may be noted. Airway stenosis can be difficult to detect, as breathlessness for other reasons can also occur in post-COVID patients, but is important not to miss. Additional complexities related to prolonged ventilatory needs include tracheostomy tube placement and potential sequelae thereof (Meister et al., 2021). Dysphagia is also common in post-COVID patients, both after intubation (Webler et al., 2022; Lindh et al., 2022), and without intubation (Marchese et al., 2022). Fortunately, post-intubation dysphagia frequently improves over time (Printza et al., 2021), but not universally, necessitating careful follow-up due to potential persistent aspiration risks. The true incidence of persistent post-COVID-19 dysphonia is unknown, but may occur through mechanisms including laryngeal and upper airway injury due to intubation or phonotrauma from coughing; impaired respiratory recruitment related to overall fatigue, airway narrowing, and/or pulmonary compromise; and problems with vocal fold mobility caused by direct mechanical intubation injury or due to post-viral recurrent laryngeal nerve weakness (Romero Arias et al., 2022). A key part of the evaluation of the larynx and upper airway for persistent throat concerns in Long COVID patients is flexible laryngoscopy. Laryngoscopy involves passing a flexible endoscope transnasally to visually assess the pharynx, hypopharynx, larynx, and subglottis for any anatomical abnormalities such as lesions, scar, tissue defects (e.g., post-intubation phonatory insufficiency), and vocal fold mobility. Patients with a history of intubation are at particular risk. If laryngoscopy is unavailable, neck imaging (preferably high-resolution CT) can also identify areas of narrowing, though sensitivity is lower. For patients with persistent cough, in addition to the diagnostic workup described for the lower airways in this chapter, it is valuable to assess for other contributing factors if clinically indicated. For example, a sinus CT scan can evaluate whether there is concurrent sinusitis exacerbating the cough. Similarly, formal evaluation for gastroesophageal reflux may include gastroenterology evaluation, upper endoscopy, pH studies, and manometry. Patients with recurrent unexplained pneumonia or symptoms of dysphagia, such as frequent coughing or throat clearing in the context of eating, drinking,

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or swallowing their saliva, should undergo instrumental evaluation of airway safety. A videofluoroscopic swallow study or modified barium swallow study or a flexible endoscopic examination of swallowing may be appropriate to rule out aspiration, along with determining potential compensatory swallowing maneuvers or diet modifications in conjunction with speech pathology to optimize swallow safety. Patients with dysphonia should also be assessed using laryngeal function studies by a speech language pathologist, including acoustic and aerodynamic measurements to objectively assess laryngeal efficiency and how air passes through the upper airway during voicing and speaking tasks. This information is used to plan an appropriate treatment approach and to track patient progress.

Treatment Medical and surgical management of upper aerodigestive tract abnormalities depends on the specific findings. For example, treatment for fungal laryngopharyngitis may be needed particularly in instances of immune compromise, hyperglycemia, antibiotic treatment, and/or systemic or inhaled corticosteroid treatment. Laryngeal granulomas can occur along the posterior true vocal fold(s) secondary to intubation and/or chronic laryngeal trauma such as chronic cough. Treatment can include reducing vocal fold trauma and reflux, and when appropriate, inhaled or injected corticosteroids, laser ablation, and surgical resection. Less commonly, unilateral vocal fold paralysis may require treatment focused on correcting associated glottic insufficiency and optimizing swallow safety. Structural upper airway obstruction may occur at the level of the true vocal folds (such as in bilateral vocal fold paralysis and/or glottic stenosis), subglottis, and/or tracheal stenosis (see Figure 5.3). Surgical and medical treatment are

Figure 5.3  Images from flexible laryngoscopy in: (A) a patient who was intubated for COVID-19 pneumonia for 3 weeks and was seen as an outpatient a few months later, showing severe subglottic stenosis, scattered sticky secretions, mild mid true vocal fold changes, and posterior laryngeal mucosal irritation. (B) a patient who had COVID-19 but was not intubated, showing a patent subglottis and visible tracheal rings.

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focused on restoring and maintaining airway patency while preserving as much voice and swallow function as possible. Surgical techniques may include procedures under local anesthesia, endoscopic transoral surgeries, tracheostomy, and/or open surgical resections (Tapias et al., 2022). Medical management such as corticosteroids, reflux reduction, and antibiotics, particularly for subglottic and tracheal stenosis, can also help reduce inflammation and reduce restenosis. Outpatient monitoring in the form of peak flow measures and symptom reporting can also be helpful. The management of patients with airway stenosis in combination with post-COVID pulmonary disease is particularly challenging due to their multifactorial and sometimes multilevel dyspnea, and benefits from multispecialty coordination that may include otolaryngology, pulmonology, thoracic surgery, anesthesiology, and primary care as well as any services necessitated by other post-COVID complications. Speech pathologists with subspecialization in voice and upper airway disorders treat post-COVID impairments related to voice, breathing, chronic coughing or throat clearing, dysphagia, and throat discomfort as part of a multidisciplinary approach (Dunn et al., 2015; Murry et al., 2006; Ryan et al., 2010). Typical areas of intervention include education regarding normal and abnormal anatomy, physiology, and behavior, laryngeal desensitization strategies, postural adjustments and respiratory re-education to help optimize breathing mechanics after deconditioning, reduce perilaryngeal hyperfunction, teach laryngeal abductory maneuvers for paradoxical vocal fold movement, and reestablish healthy phonatory patterns. Outcomes of speech pathology interventions specifically targeting Long COVID symptoms are still emerging, but successful cases include post-COVID paradoxical vocal fold movement (El Kik et al., 2022 and Garg et al., 2022). Successful pilot programs such as SingStrong have been developed to treat Long COVID through mindfulness, respiratory retraining, vocal exercises, and singing (Cahalan et al., 2022). Some patients benefit from both respiratory re-education through physical therapy and speech pathology treatment for muscular deconditioning and improving respiratory coordination. There is also a role for speech pathology in treating dyspnea which is not severe enough to qualify for respiratory rehabilitation (e.g., normal PFTs and imaging, with persistent symptoms) but significantly impacts quality of life. Similarly, speech pathologists can help facilitate improved patient communication via tracheostomy speaking valves with or without ventilator use, care and maintenance of tracheostomies, and eventual capping trials with retraining of the oral and nasal airway if decannulation becomes increasingly likely (Wiberg et al., 2020).

Conclusion Patients with a history of COVID-19 may present with several upper and lower respiratory complaints. Thorough history and physical examination are critical in determining additional steps in evaluation and management. The exacerbation of preexisting chronic pulmonary and extrapulmonary conditions can overlap with symptoms related to SARS CoV-2 infection; therefore,

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differential diagnosis should be broad. Upper airway disease can contribute to dyspnea and cough commonly seen in Long COVID patients. Given the complexity of both the evaluation and management of both upper and lower respiratory pathology in COVID-19 recovery, a multidisciplinary approach is beneficial for most patients. Patient participation in rehabilitation, including speech therapy and pulmonary rehabilitation, has been shown to improve dyspnea and cough. Medical therapy for many respiratory Long COVID symptoms remains poorly studied, and patients should be encouraged to enroll in appropriate clinical studies.

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84  Respiratory System sequelae of SARS-CoV-2 infection. American Heart Journal Plus: Cardiology Research and Practice, 18, 100176. https://doi​.org​/10​.1016​/j​.ahjo​.2022​.100176 Waxman, A., Restrepo-Jaramillo, R., Thenappan, T., Ravichandran, A., Engel, P., Bajwa, A., ... & Nathan, S. D. (2021). Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. New England Journal of Medicine, 384(4), 325–334. Webler, K., Carpenter, J., Hamilton, V., Rafferty, M., Cherney, L. (2022). Dysphagia characteristics of patients post SARS-CoV-2 during inpatient rehabilitation. Archives of Physical Medicine and Rehabilitation, 103(2), 336–341. https://doi​.org​/10​.1016​/j​.apmr​ .2021​.10​.007 Wiberg, S., Whitling, S., Bergstrom, L. (2020). Tracheostomy management by speechlanguage pathologists in Sweden. Logopedics Phoniatrics Vocology, 26:1–11. https://doi​.org​ /10​.1080​/14015439​.2020​.1847320. Wigén, J., Löfdahl, A., Bjermer, L., Rendin, L. E., & Westergren-Thorsson, G. (2020). Converging pathways in pulmonary fibrosis and Covid-19-the fibrotic link to disease severity. Respiratory Medicine: X, 2, 100023. Wootton, S. C., Kim, D. S., Kondoh, Y., Chen, E., Lee, J. S., Song, J. W., ... & Collard, H. R. (2011). Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 183(12), 1698–1702. Xie, J., Prats-Uribe, A., Feng, Q., Wang, Y., Gill, D., Paredes, R., & Prieto-Alhambra, D. (2022a). Clinical and genetic risk factors for acute incident venous thromboembolism in ambulatory patients with COVID-19. JAMA Internal Medicine. Advance online publication. https://doi​.org​/10​.1001​/jamainternmed​.2022​.3858 Xie, Y., Xu, E., Bowe, B., & Al-Aly, Z. (2022b). Long-term cardiovascular outcomes of COVID-19. Nature Medicine, 28(3), 583–590. https://doi​.org​/10​.1038​/s41591​-022​ -01689-3 Zanetti, G., Hochhegger, B., & Marchiori, E. (2013). Organizing pneumonia as a pulmonary sequela of swine flu. Lung India, 30(2), 171. Zhang, F., Wei, Y., He, L., Zhang, H., Hu, Q., Yue, H., ... & Dai, H. (2022). A trial of pirfenidone in hospitalized adult patients with severe coronavirus disease 2019. Chinese Medical Journal, 135(03), 368–370.

6

Gastrointestinal Disorders Sonia Villapol, PhD

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19 or COVID). SARS-CoV-2 replicates and subsequently infects cells, mainly in the upper respiratory tract but in many other tissues as well. COVID affects not only the respiratory and cardiovascular systems, but also the central nervous system (CNS) and the gastrointestinal (GI) tract (Villapol, 2020), suggesting that SARS-CoV-2 infection may spread beyond the respiratory system. Epidemiological studies describe different phases in the development of COVID. Shortly after infection, the early or viral phase is marked by a high viral load and reduced inflammatory activity, with hardly any symptoms that are also associated with GI diseases. During the progressive or late phase of infection, people who are positive for COVID develop the most severe symptoms, such as respiratory problems and fever (Figure 6.1). The detection of GI symptoms early in the disease could lead to slower transmission and open the door to novel treatments that could reduce the severity of COVID. A recent study showed that 1 in 5 people who tested positive for COVID-19 had at least one gastrointestinal symptom, such as diarrhea, vomiting, or belly pain. Of those hospitalized, 25.9% had gastrointestinal issues (Rogers et al., 2021). Changes in gut microbiome were associated with GI symptoms after SARS-CoV-2 infection. Intestinal bacteria play a fundamental role in regulating the immune system and are the target of future treatments for COVID. This chapter seeks to concisely address post-COVID GI manifestations, to provide a summary of pathophysiological mechanisms underlying GI involvement, and to provide an overview of the immune changes in the GI tract and their association with the development of COVID severity. It also examines how COVID alters the intestinal microbiome and promotes persistent gut microbiome dysbiosis in COVID survivors. Understanding these mechanisms will help researchers design treatments focused on eliminating viral reservoirs in the gut to reduce COVID symptoms acutely or in the long term.

DOI: 10.4324/9781003371090-6

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Figure 6.1 Illustrative model of SARS-CoV-2 infection and its association with the lung-gutbrain axis and microbiome dysbiosis. Angiotensin-converting enzyme II (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in multiple human host tissues, including the esophagus, lungs, liver, kidneys, brain, colon, or small intestine epithelium. SARS-CoV-2 activates intestinal ACE2 receptors, induces inflammation (enteritis) and, ultimately, diarrhea. These tissues are the targets of SARS-CoV-2, which goes through acute COVID where a high viral load induces intestinal problems, acute respiratory distress syndrome (ARDS) appears, and inflammation from the cytokine storm increases considerably. At the same time, microbiome dysbiosis occurs by altering the T and B cells of the intestinal immune system and activating the enteric system that sends inflammatory signals to the circulatory current or other organs including the brain. During Long Covid, ARDS decrease, but the inflammation and chronic inflammation persist. Created with Biorender​.c​om and adapted from (Villapol, 2020).

Tropism and Gastrointestinal Pathophysiology of SARS-CoV-2 We need a better understanding of the GI symptomatology caused by SARSCoV-2. In addition, the pathophysiological mechanism that triggers the GI and hepatic manifestations of COVID is not well established. SARS-CoV-2 enters cells mainly through the binding of spike (S) protein to angiotensin-converting enzyme II (ACE2) receptors on infected cells through the mechanisms of cell tropism (Hoffmann et al., 2020). The ACE2 receptor is expressed in type II

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alveolar epithelial cells of the lung, arterial and venous endothelial cells, and smooth muscle cells of the stomach, small intestine, colon, skin, thymus, spleen, kidney, liver, and brain, among others (Li et al., 2020). The highest level of ACE2 mRNA expression was observed in the intestine, exhibited heterogeneous expression patterns in the GI tract, and showed a punctate distribution in liver cells (An et al., 2021). Thus, SARS-CoV-2 activity could cause ACE2 modifications in the intestine, increasing susceptibility to intestinal inflammation and diarrhea. An autopsy series of COVID patients recently demonstrated consistent evidence of SARS-CoV-2 infection of the small intestine; they also recovered live virus from these intestinal biopsies. In addition to using ACE2, the triumphant entry of SARS-CoV-2 depends on cellular serine protease 2 (TMPRSS2), which adheres the S protein of the coronavirus to the cell membrane of the host cell. TMPRSS2 is also expressed in the ileum and colon, and in the epithelial cells of the small intestine (D’Amico et al., 2020) suggesting that the virus can invade the entire GI tract. High co-expression of ACE2 and TMPRSS2 was detected in enterocytes, esophagus, and lungs (Hoffmann et al., 2020), and was highest in the small intestine, with 20% expressed in enterocytes and 5% in colon cells.

Gastrointestinal Symptoms during Acute COVID Although most COVID patients have fever coupled with respiratory symptoms and signs, such as cough and dyspnea, GI manifestations such as diarrhea, anorexia, nausea, vomiting, and abdominal pain are common. The combined incidence of GI symptoms in people hospitalized with COVID, such as nausea, vomiting, and diarrhea, is estimated to be between 11% and 18%. Diarrhea is one of the most frequent GI symptoms; clinical studies report an incidence ranging from 2 to 50% of cases, and it may even precede respiratory symptoms. GI symptoms correlate with a risk of clinical deterioration of COVID. A total of ten GI symptoms were reported. The most frequent GI manifestations were nausea or vomiting (13.1%), diarrhea (11.05%), anorexia (8.7%), and abdominal pain (2.4%), respectively (Alzahrani et al., 2022). Anorexia was the most common GI symptom in adults. At the same time, diarrhea was reported as the most common symptom in adults and children, and vomiting was more common in children than in adults. GI symptoms are commonly seen in patients with COVID, with a prevalence of up to 31.9% in adults. The prevalence of GI symptoms in neonates, children, adolescents, or pregnant women is less than 20% and does not differ from the general population (Luo et al., 2022). The relationship between diarrhea and COVID severity was regionally different, but the increased risk of nausea and vomiting needs to be verified (Zeng et al., 2022). Interestingly, several case-control studies suggested that COVID patients with GI symptoms might be at increased risk of clinical deterioration. More clinical studies are required to elucidate the percentage of patients with COVID who develop intestinal symptoms and whether these depend on other factors such as age, gender, or other comorbidities. We know advanced

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age could significantly predict poor prognosis in COVID patients with GI symptoms. However, there is no convincing evidence that GI symptoms may be associated with an increased risk of mortality in patients with COVID (Wang et al., 2022).

Gastrointestinal Symptoms during Long Covid Post-acute sequelae of SARS-CoV-2 infection (PASC) or “Long COVID” is an unusual constellation of symptoms even after recovery from SARS-CoV-2 respiratory infection. GI symptoms are expected to be resolved 6 months after recovery from the acute respiratory symptoms of COVID. However, 10–25% of patients report persistent GI symptoms (Blackett et al., 2022). In persistent GI symptoms, an increase in diagnoses such as diseases of the esophagus, abdominal pain, diarrhea, and irritable bowel syndrome was identified, as well as increased use of laxatives, histamine receptor antagonists, and acid-suppressing medications (Al-Aly et al., 2021). Common GI sequelae in severely ill patients with COVID after 3 months of hospital discharge include loss of appetite (24%), nausea (18%), acid reflux (18%), and diarrhea (15%). Less common GI sequelae included abdominal distention (14%), belching (10%), vomiting (9%), abdominal pain (7%), and bloody stools (2%) (Weng et al., 2021) (Figure 6.2). COVID long-haulers were more impaired than the myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) group for many symptoms within the immune and orthostatic domains, and it does appear that GI symptoms are worse in ME/CFS than among Long Covid patients (Jason et al., 2021). However, GI distress does appear to be a cardinal symptom of ME/CFS based on a large and international factor analytic study (Conroy et al., 2022). The GI tract is another site where viral infections may persist chronically. Epstein–Barr virus (EBV) can be detected in the gastric epithelium and causes infectious mononucleosis that can lead to CFS. The reactivation of EBV and SARSCoV-2 RNAemia are predictors of Long Covid, and those reporting GI Long Covid symptoms (Y. Su et al., 2022). GI symptoms might be a marker for those who are worse after infection from EBV (Jason et al., 2021). Treating persistent GI symptoms is important for properly managing patients in post-COVID health units and resources. Therefore, the prolonged presence of SARS-CoV-2 in the GI tissue may also impact multiple sequelae of Long Covid; thus, GI care and nutritional support for patients after hospitalization for COVID is necessary (Weng et al., 2021).

Hepatic Symptomatology and Pathophysiology of COVID COVID causes various GI symptoms, with the consequent elevation of liver enzymes. Liver enzymes appear elevated in patients with COVID, but it does not seem to affect mortality or the rate of admission to intensive care units (Shehab et al., 2021). Liver injury defined by elevated serum aminotransferase

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Figure 6.2 Gastrointestinal and hepatic manifestations of acute and post-COVID. The SARS-CoV-2 infection causes gastrointestinal disturbances in both acute and Long Covid. Gastrointestinal and hepatic manifestations are associated with the nasopharyngeal, oral, esophageal, gastric, hepatobiliary, pancreatic, intestinal, and colonic systems. Created with Biorender​.co​m.

levels has been observed after infection with previous coronaviruses, such as SARS and MERS (Alsaad et al., 2018; Chau et al., 2004). In patients who died from COVID, the virus was detected in the lungs of all patients, while only 44% of patients had the virus detected in the liver (Chornenkyy et al., 2021). COVID patients showed varying degrees of liver dysfunction (Mao et al., 2020) and multifactorial disorders (Aleem & Shah, 2021). In the liver,

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cholangiocytes and hepatic endothelial cells have been identified as the target cells of SARS-CoV-2 (Jothimani et al., 2020). In addition, steatosis, multifocal hepatic necrosis without inflammatory cell infiltration, and canalicular cholestasis have been described in liver biopsies from patients with COVID. Sinusoidal dilatation is attributed to the deceleration of cardiogenic venous outflow. It is well known that hypoxia and impaired cardiovascular function predispose the liver to injury (Ahmad et al., 2021; Pirisi et al., 2021; Premkumar & Kedarisetty, 2021; Zippi et al., 2020). Patients with severe COVID experience significant transcriptional changes in the liver that can result in tissue remodeling, mitochondrial dysfunction, inferior hepatomegaly, and detoxification resulting in clinically observed liver dysfunction (Hammoudeh et al., 2021). Among patients hospitalized with symptomatic COVID disease, abnormal liver function tests range from 14% to 53%. A correlation between the severity of COVID and liver function abnormalities has been reported. The most frequently observed anomalies were hypoalbuminemia, elevated γ-glutamyltransferase, mild aminotransferase elevations, and hyperbilirubinemia (Hassanipour et al., 2020; Kulkarni et al., 2020) in patients hospitalized in intensive care units and patients requiring ventilation. Aspartate aminotransferase levels correlate strongly with alanine aminotransferase levels throughout the disease, suggesting a hepatocellular origin (Bloom et al., 2021a). Notably, the prevalence of elevated aminotransferases was substantially higher among patients with severe COVID disease (45.5%) than those with mild disease (15%). In addition, increased bilirubin levels and liver stiffness were associated with more severe outcomes (Bloom et al., 2021b). Although liver function abnormalities are commonly seen and correlate with mortality, acute liver failure is infrequent among COVID patients without underlying chronic liver diseases, and more typically associated with severe pneumonia and multi-organ dysfunction (Schattenberg et al., 2020). The prevalence of abnormal liver functions among asymptomatic patients with SARS-CoV-2 infection is unknown. Liver damage in mild cases of COVID appears to be transient (Deane et al., 2021; Musa, 2020) even though elevated liver enzymes appear. Liver consequences of SARS-CoV-2 infection are more clinically relevant in patients with pre-existing cirrhosis who are at notably high risk of severe COVID and death (Marjot et al., 2021). Several potential mechanisms in the pathophysiology of hepatic manifestations have been postulated, including direct viral insult, exacerbation of the underlying liver disease, hyperinflammatory states, and drug-induced injury (Grande et al., 2020). The liver plays an important role in the regulation of immune homeostasis. Patients with cirrhosis may have dysregulated innate and acquired immunity and thus may be at higher risk of COVID-related complications, Long Covid, and death (Singh & Khan, 2020). Possible reasons include direct liver involvement due to the virus, drug-induced liver injury due to various therapeutic agents, hypotension, and associated underlying liver disease (e.g., cirrhosis due to multiple etiologies, alcoholic steatohepatitis, non-alcoholic fatty liver disease, and viral hepatitis).

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Prolonged Fecal Shedding of SARS-CoV-2 in Patients with COVID The frequency, amount, and duration of viral RNA shed in feces are valuable for inferring population-level COVID prevalence from wastewater studies to inform public health measures. The detection of variants of concern in wastewater samples is essential to monitor the emergence and spread of variants and inform public health response (Sapoval et al., 2022). We must understand how respiratory virus shedding and SARS-CoV-2 RNA transmissibility are temporally related to fecal viral RNA shedding. In addition, identifying fecal coronavirus RNA may also lead researchers to ask new questions, such as can SARS-CoV-2 in fecal samples be transmitted? Since the genetics of SARSCoV-2 is like that of SARS-CoV that had confirmed fecal-oral transmission, the possibility of a similar transmission route remains to be determined. There is evidence that SARS-COV-2 can also be transmitted via the fecal-oral route (Cuicchi et al., 2021). Viral strains were found in feces (Xu et al., 2020), but there is some controversy on whether the viral load was infectious or provides examples of transmission. SARS-CoV-2 (including live viruses with infective capacity) was found in feces (Sun et al., 2020); however, detecting viral RNA in fecal samples does not necessarily indicate that viable infectious virions are present or that they can be transmitted via the fecal route. It is also unclear whether the presence of contagious SARS-CoV-2 virions in feces is rare or common. Another analysis of 17 studies also detected SARS-CoV-2 RNA in patient fecal samples by an average of 43% (Wong et al., 2020). The viral load of coronavirus appeared in the feces of 54% of infected patients (Xie et al., 2020). Furthermore, fecal shedding of SARS-CoV-2 RNA is positively associated with most GI and specific systemic and respiratory symptoms. Patients who shed viral RNA in their stool were more likely to report nausea, vomiting, abdominal pain, and inflammatory diarrhea (Xiao et al., 2020). Respiratory and systemic symptoms, including nasal discharge, headaches, and body aches, were also related to the presence of fecal SARS-CoV-2 RNA (Natarajan et al., 2022). Interestingly, in the few studies investigating longitudinal fecal samples, prolonged fecal shedding of SARS-CoV-2 RNA can occur even after respiratory shedding ceases. Although the shedding of SARS-CoV-2 RNA in the respiratory tract and feces may be prolonged, the lifespan of a viable virus is relatively short (Cevik et al., 2021). One longitudinal study looked at the dynamics of fecal RNA shedding up to 10 months after COVID diagnosis in patients with mild to moderate disease (Natarajan et al., 2022), revealing important insights into disease pathophysiology. Fecal SARS-CoV-2 RNA was detected in 50% of participants within the first week after diagnosis, 12% of participants continued to shed SARS-CoV-2 RNA in feces at 4 months after diagnosis, and 4% of participants cleared at 7 months. This study also found that GI symptoms (e.g., abdominal pain, nausea, or vomiting) are associated with fecal shedding of SARS-CoV-2 RNA.

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SARS-CoV-2 RNA can also be detected through GI samples from children for more than 70 days (Benvari et al., 2022). However, the duration of viral shedding could be mainly due to the host’s immune status, leading to more prolonged viral shedding. The lower prevalence could be because children may present with GI symptoms more frequently than adults, and a higher proportion of fecal SARS-CoV-2 RNA is observed in patients with GI manifestations (Benvari et al., 2022). Persistent GI symptoms are important for properly managing patients in post-COVID health units and resources. Therefore, the prolonged presence of SARS-CoV-2 in the GI tissue may also impact multiple sequelae of Long Covid; thus, GI care and nutritional support for patients after hospitalization for COVID are necessary (Weng et al., 2021).

The Impact of the Gut Microbiome on Long COVID The human gut microbiome consists of trillions of diverse bacteria that inhabit the gut, exerting many effects on the regulatory mechanisms of immune response and metabolism (Kho & Lal, 2018). Current epidemiological evidence establishes that the so-called gut-lung axis strongly influences the local and systemic microbiota impact, autoimmune diseases, and moderate to severe infections. This gut-lung axis is a bidirectional relationship between the populations of microorganisms in the lung and GI epithelium that antibiotic use can modify. Our microbiome changes as we age to favor less diversity and a more significant inflammatory state. COVID appears more dangerous in older people, men, and comorbidities (Fuchs et al., 2018). Furthermore, diabetes is another disease associated with increased severity of symptoms and complications of COVID, and this can be attributed to systemic inflammation and gutmetabolite dysfunction (Heintz-Buschart et al., 2016). Cardiovascular disease is accompanied by an imbalance of gut microbiota and a decreased microbiome diversity (Anselmi et al., 2020; Jayachandran et al., 2019; Novakovic et al., 2020). Hypertension is likely influenced by diet, lifestyle factors, and the microbiome (Louca et al., 2020). Notably, an increase in short-chain fatty acids (SCFA) was previously associated with decreased blood pressure and improved arterial compliance (Chen et al., 2020). Alterations of the intestinal microbiome, such as decreased bacterial diversity, reduced numbers of protective microorganisms, and bacterial translocation, lead to impaired intestinal epithelial integrity, decreased mucus secretion, altered synthesis and secretion of antimicrobial agents, and infection. The gut microbiota’s role is in a symbiotic relationship with its host, facilitating the synthesis of vitamins and the fermentation of carbohydrates and other nutrients, and regulating mucosal permeability and immune response. Gut dysbiosis may be defined as an imbalance in the normal composition of the microbiome, and is commonly found in multiple inflammatory diseases (Fiorindi et al., 2022) associated with increased disease severity. Intestinal microbiota alterations and dysbiosis have already been detected in several ME/CFS studies. Higher levels of pro-inflammatory bacterial species such as Enterobacteriaceae

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and Streptococcus, and lower levels of the beneficial Bifidobacteria and a decrease in anti-inflammatory Firmicutes have been detected in ME/CFS patients (Konig et al., 2021). SARS-CoV-2 infection in epithelial cells of the GI system has been also associated with dysbiosis of the bacterial microbiota (Zhu et al., 2022). Primary inflammatory stimuli trigger the release of microbial products and cytokines, causing microbial dysbiosis that can induce an inflammatory environment, releasing intestinal cytokines into the circulatory system, and increasing the systemic inflammation of COVID (Villapol, 2020). It is essential to investigate how gut bacteria in response to SARS-CoV-2 infection interacts in the inflammation and pathogenesis of COVID. Post-COVID GI symptoms accompany intestinal inflammation or damage, loss of gut barrier integrity, and gut microbes that can activate innate and adaptive immune cells to release proinflammatory cytokines into the circulatory system, leading to systemic inflammation (Figure 6.1). Dysbiosis has been observed in patients with COVID in the long term, up to 12 months post-infection (Q. Su et al., 2022). It remains unknown whether PACS-associated gut dysbiosis would also linger for such a long time or related to COVID alone or may be due to motility-related diarrhea and/or the use of antibiotics, antivirals, or other treatments the patients received when they were hospitalized. A significantly reduced bacterial diversity (Gu et al., 2020b) and a reduced alpha microbial diversity (Zhang et al., 2020) have been demonstrated in COVID patients. Understanding the composition of the intestinal microbiota or bacteria and their metabolic products in the context of COVID can help determine new biomarkers of the disease and help identify new therapeutic targets (Chen et al., 2021). Elucidating changes in the microbiome as reliable biomarkers in the context of COVID represents an overlooked piece of the disease puzzle and requires further investigation.

Microbiome Profiling in COVID and PASC Patients Bacteria in the bowel of healthy individuals consists of Bacteroidetes (e.g., Bacteroides) and Firmicutes (e.g., Lactobacillus, Bacillus, and Clostridium), with a lower number of Actinobacteria (e.g., Bifidobacterium) and Proteobacteria (e.g., Escherichia) (Human Microbiome Project, 2012) (Figure 6.3). The relative abundance differences of these microbes within healthy individuals have been previously defined as enterotypes (Arumugam et al., 2011). Microbiomes during the acute phase of COVID showed a loss of microbiome diversity and subsequent prolongation of the disease. A study has shown that 14 bacterial species significantly associated with SARS-CoV-2 fecal viral load were identified in all fecal samples (Guo et al., 2020). The gut microbiome composition of patients with COVID in the convalescent phase was enriched in Bifidobacterium dentium and Lactobacillus ruminis, while being deficient in Eubacterium rectale, Ruminococcus bromii, Bifidobacterium longum, and Faecalibacterium prausnitzii (Yeoh et al., 2021). Ruminococcus gnavus was identified in COVID patients and

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Figure 6.3 COVID-induced intestinal microbial dysbiosis. SARS-CoV-2 infection induces changes in intestinal bacteria. An increase in the relative abundance of some species of bacteria and a reduction in others has been identified as associated with Covid in the acute and long term. Created with Biorender​.co​m.

positively correlated with inflammatory markers, while Clostridia was negatively correlated (Gou W et al., 2020). The severity of COVID correlates positively with the relative abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi, while the abundance of Faecalibacterium prausnitzii, associated with an anti-inflammatory microenvironment, is inversely correlated to the severity of the disease (Zuo, Zhang, et al., 2020). During hospitalization, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus were detected in COVID patients, which inversely correlated with SARS-CoV-2 load in fecal samples (Zuo, Zhan, et al., 2020) (Figure 6.3). Fecal samples with a high SARS-CoV-2 infectivity signature had higher abundances of the bacterial species Collinsella aerofaciens, Collinsella tanakaei, Streptococcus infantis, and Morganella morganii. In contrast, fecal samples with low or no infectivity signature for SARS-CoV-2 had a higher abundance of SCFA-producing bacteria with protective function such as

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Parabacteroides merdae, Bacteroides stercoris, Alistipes onderdonkii, and Lachnospiraceae bacteria (Zuo et al., 2021). SARS-CoV-2 infection also increases the number of opportunistic pathogens such as Clostridium hathewayi, Actinomyces viscosus, Streptococcus, and Veillonella, along with a reduction in beneficial bacteria, including Faecalibacterium prausnitzii, which is one of the butyric acid-producing bacteria (Gu et al., 2020a) (Figure 6.3). Post-acute COVID individuals also show gastrointestinal alterations (e.g., nausea, diarrhea, and abdominal and epigastric pain). It has also been demonstrated that the intestinal microbiomes of these patients show higher levels of Ruminococcus gnavus and Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Patients who had no persistent symptoms showed a gut microbiome profile comparable to that of non-COVID-19 controls (Liu et al., 2022). These studies open the door to possible interventions for the gut microbiota in hospitalized patients to reduce the severity of COVID. A gut microbiome profile associated with COVID severity and changes in fecal shedding of SARSCoV-2 has been established (Zuo, Zhan, et al., 2020). The disturbance in levels or composition of SCFA-producing bacteria may influence pathologic processes. SCFA-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii, were characterized by the most significant negative correlations with PASC. Another study revealed that gut microbiome composition in patients with PASC, compared with uninfected individuals, was enriched in bacteria species Bacteroides vulgatus and Ruminococcus gnavus while being reduced in Eubacterium rectale, Blautia obeum, Collinsella aerofaciens, and Faecalibacterium prausnitzii 6 months after being admitted to the hospital (Liu et al., 2022). The microbiota could play a pivotal role as a biomarker of susceptibility of SARS-CoV-2 infection. Therefore, further studies investigating the correlation between SARS-CoV-2 and intestinal inflammation are needed, including histopathology and molecular diagnostic assessments.

Diet and Gut Microbiota-Based Therapeutic Approaches for Long Covid Gastrointestinal Symptoms There is currently no evidence for or against any specific management strategy for Long Covid GI symptoms. At the same time, applying specific treatments directed to the GI tract could be considered a therapeutic option in parallel with antiviral or anti-inflammatory therapies. If we block the entry mechanisms of SARS-CoV-2 in the intestinal tract, and especially when we better understand the progression of the disease, we will be able to design new treatments that can mitigate the results of the disease. The commensal microbiome forms a dynamic environment that can be altered and cause dysbiosis from virus infection but can be positively modulated by diet components and probiotic treatments (Ashuro et al., 2020; Illiano et al., 2020; Sirisinha, 2016). Several studies show that an optimal immune response depends on proper diet and nutrition to control SARS-CoV-2 infection (Zuo, Zhan, et al., 2020;

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Zuo, Zhang, et al., 2020). Consideration of the dietary and nutritional components, the factors during viral infection, can strengthen the immune system to prevent infections. An adequate and balanced diet is a meaningful basis for an immune response. Intake of a sufficient amount of protein is crucial for producing antibodies. Also, a low vitamin A or zinc level has been associated with an increased risk of infection. Nutritional dietary components known to exert anti-inflammatory and antioxidant properties include omega-3 fatty acids with high anti-inflammatory and antioxidant capacity, vitamin C, vitamin E, and phytochemicals such as carotenoids and polyphenols widely present in plant-based foods (Allison et al., 2019). An optimal state of proper nutrients reduces inflammation and oxidative stress, thus strengthening the immune system to protect us from the severity of COVID (Zabetakis et al., 2020). A study of older men with pre-existing conditions and below-normal vitamin D levels concluded that they were 13 times more likely to die of COVID (Quesada-Gomez et al., 2020). Further, it is important to investigate the effect of high-fiber diets on the outcome of SARS-CoV-2 infection. Using prebiotics and probiotics to regulate the balance of the intestinal microbiota could be an effective treatment to reduce the risk of bacterial and viral infections (Conte & Toraldo, 2020). Design treatments for COVID would be based on the administration of probiotics and prebiotics (Molino et al., 2021), or nutrients that would replace the absent bacteria, thus avoiding the risk of systemic infection. Intestinal bacteria also play a fundamental role in the brain-gut axis and regulate neurological functions such as depression or anxiety (Fung et al., 2017). Plant-based fiber has prebiotic effects, including promoting the growth of bacteria associated with health benefits, such as Bifidobacterium and Lactobacillus spp. Moreover, plant-based fiber reduces potential pathogens such as Clostridium spp. Adequate fiber intake has been shown to decrease the relative risk of mortality from infectious and respiratory diseases by 20 to 40% and was associated with a lower risk of chronic obstructive pulmonary disease (Baud et al., 2020). Probiotics are live microorganisms or beneficial bacteria used to benefit the host’s health, modulating the composition and function of the intestinal microbiota. Using prebiotics and probiotics to regulate the balance of the intestinal flora could be an effective treatment to reduce the risk of bacterial and viral infections (Conte & Toraldo, 2020). Design treatments for COVID would be based on the administration of both probiotics and prebiotics, or nutrients that would replace the absent bacteria, thus preventing the risk of systemic infection. The impact of probiotics should also be investigated in COVID, as some may help by interacting with the intestinal microbiota and modulating the immune system. Gut microbiota could represent a new therapeutic target, and probiotics could have a role in managing COVID patients. With an adequate probiotic cocktail, the inflammatory response resulting from SARS-CoV-2 infection could be significantly reduced, thereby reducing the disease’s severity. This crucial aspect of probiotic bacteria presents a unique opportunity to manage COVID because redox homeostasis is pivotal in inhibiting disease

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progression. Therefore, detailed research with a different combination of probiotic strains having a specific effect on the virus is necessary for therapeutic implementation. Possible considerations for using the gut microbiome in COVID as a diagnostic or therapeutic tool have not yet been explored (Singh & Rao, 2021). Therapeutics with defined microbes will offer greater confidence in the treatments’ power and risk mitigation for improved patients.

Conclusion SARS-CoV-2 can induce GI manifestations in acute, post-acute, and late phases of COVID. We need to identify the GI symptoms associated with the specific phases of the disease to reverse or alleviate the severity of the symptomatology of Long Covid patients. The dysregulation of the immune system of COVID patients would help elucidate the characteristics of immunity associated with GI and liver problems. A therapeutic option could be modifying intestinal bacteria or their metabolic products during the acute or postacute phase of COVID. Specifically, the symptoms associated with long-term COVID need to be deeply studied, and the design of a diet for these patients that can strengthen the immune system is essential. In conclusion, we must highlight the importance of investigating GI and liver disorders in COVID patients to facilitate a better diagnosis and seek therapeutic targets that reduce severe disease, such as those probiotics that can modify the bacterial microbiota. GI and hepatic alterations should be analyzed not only in the acute phase of the disease, but also the post-acute phase or persistent COVID. Further studies are warranted to determine the underlying pathophysiological alterations of the GI tract’s involvement in the postCOVID conditions. Signs or symptoms must be recognized to manage, to provide treatment, and to prevent future associated pathologies from being triggered.

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102  Gastrointestinal Disorders Natarajan, A., Zlitni, S., Brooks, E. F., Vance, S. E., Dahlen, A., Hedlin, H., Park, R. M., Han, A., Schmidtke, D. T., Verma, R., Jacobson, K. B., Parsonnet, J., Bonilla, H. F., Singh, U., Pinsky, B. A., Andrews, J. R., Jagannathan, P., & Bhatt, A. S. (2022, Jun 10). Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med, 3(6), 371–387, e379. https://doi​.org​/10​.1016​ /j​.medj​.2022​.04​.001 Novakovic, M., Rout, A., Kingsley, T., Kirchoff, R., Singh, A., Verma, V., Kant, R., & Chaudhary, R. (2020, Apr 26). Role of gut microbiota in cardiovascular diseases. World J Cardiol, 12(4), 110–122. https://doi​.org​/10​.4330​/wjc​.v12​.i4​.110 Pirisi, M., Rigamonti, C., D'Alfonso, S., Nebuloni, M., Fanni, D., Gerosa, C., Orru, G., Venanzi Rullo, E., Pavone, P., Faa, G., Saba, L., & Boldorini, R. (2021, Feb). Liver infection and COVID-19: The electron microscopy proof and revision of the literature. Eur Rev Med Pharmacol Sci, 25(4), 2146–2151. https://doi​.org​/10​.26355​/eurrev​_202102​ _25120 Premkumar, M., & Kedarisetty, C. K. (2021, Apr 28). Cytokine storm of COVID-19 and its impact on patients with and without chronic liver disease. J Clin Transl Hepatol, 9(2), 256–264. https://doi​.org​/10​.14218​/JCTH​.2021​.00055 Quesada-Gomez, J. M., Castillo, M. E., & Bouillon, R. (2020, Jun 11). Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166. J Steroid Biochem Mol Biol, 105719. https://doi​.org​/10​.1016​/j​.jsbmb​.2020​.105719 Rogers, H. K., Choi, W. W., Gowda, N., Nawal, S., Gordon, B., Onyilofor, C., Rogers, C. M., Yamane, D., & Borum, M. L. (2021, Oct). Frequency and outcomes of gastrointestinal symptoms in patients with Corona Virus Disease-19. Indian J Gastroenterol, 40(5), 502–511. https://doi​.org​/10​.1007​/s12664​-021​-01191-7 Sapoval, N., Liu, Y., Lou, E. G., Hopkins, L., Ensor, K. B., Schneider, R., Stadler, L. B., & Treangen, T. J. (2022, Jul 22). Enabling earlier detection of recently emerged SARSCoV-2 variants of concern in wastewater. medRxiv. https://doi​.org​/10​.1101​/2021​.09​ .08​.21263279 Schattenberg, J. M., Labenz, C., Worns, M. A., Menge, P., Weinmann, A., Galle, P. R., & Sprinzl, M. F. (2020, Aug). Patterns of liver injury in COVID-19: A German case series. United European Gastroenterol J, 8(7), 814–819. https://doi​.org​/10​.1177​ /2050640620931657 Shehab, M., Alrashed, F., Shuaibi, S., Alajmi, D., & Barkun, A. (2021, Mar). Gastroenterological and hepatic manifestations of patients with COVID-19, prevalence, mortality by country, and intensive care admission rate: Systematic review and metaanalysis. BMJ Open Gastroenterol, 8(1). https://doi​.org​/10​.1136​/bmjgast​-2020​-000571 Singh, K., & Rao, A. (2021, Mar). Probiotics: A potential immunomodulator in COVID-19 infection management. Nutr Res, 87, 1–12. https://doi​.org​/10​.1016​/j​.nutres​.2020​.12​.014 Singh, S., & Khan, A. (2020, Aug). Clinical characteristics and outcomes of coronavirus disease 2019 among patients with preexisting liver disease in the United States: A multicenter research network study. Gastroenterology, 159(2), 768–771. e763. https://doi​ .org​/10​.1053​/j​.gastro​.2020​.04​.064 Sirisinha, S. (2016, Dec). The potential impact of gut microbiota on your health:Current status and future challenges. Asian Pac J Allergy Immunol, 34(4), 249–264. https://doi​.org​ /10​.12932​/AP0803 Su, Q., Lau, R. I., Liu, Q., Chan, F. K. L., & Ng, S. C. (2022, Aug 8). Post-acute COVID19 syndrome and gut dysbiosis linger beyond 1 year after SARS-CoV-2 clearance. Gut. https://doi​.org​/10​.1136​/gutjnl​-2022​-328319

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Su, Y., Yuan, D., Chen, D. G., Ng, R. H., Wang, K., Choi, J., Li, S., Hong, S., Zhang, R., Xie, J., Kornilov, S. A., Scherler, K., Pavlovitch-Bedzyk, A. J., Dong, S., Lausted, C., Lee, I., Fallen, S., Dai, C. L., Baloni, P., Smith, B., Duvvuri, V. R., Anderson, K. G., Li, J., Yang, F., Duncombe, C. J., McCulloch, D. J., Rostomily, C., Troisch, P., Zhou, J., Mackay, S., DeGottardi, Q., May, D. H., Taniguchi, R., Gittelman, R. M., Klinger, M., Snyder, T. M., Roper, R., Wojciechowska, G., Murray, K., Edmark, R., Evans, S., Jones, L., Zhou, Y., Rowen, L., Liu, R., Chour, W., Algren, H. A., Berrington, W. R., Wallick, J. A., Cochran, R. A., Micikas, M. E., Unit, I. S.-S. C.-B., Wrin, T., Petropoulos, C. J., Cole, H. R., Fischer, T. D., Wei, W., Hoon, D. S. B., Price, N. D., Subramanian, N., Hill, J. A., Hadlock, J., Magis, A. T., Ribas, A., Lanier, L. L., Boyd, S. D., Bluestone, J. A., Chu, H., Hood, L., Gottardo, R., Greenberg, P. D., Davis, M. M., Goldman, J. D., & Heath, J. R. (2022, Mar 3). Multiple early factors anticipate post-acute COVID-19 sequelae. Cell, 185(5), 881–895. e820. https://doi​.org​/10​.1016​ /j​.cell​.2022​.01​.014 Sun, X., Wang, T., Cai, D., Hu, Z., Chen, J., Liao, H., Zhi, L., Wei, H., Zhang, Z., Qiu, Y., Wang, J., & Wang, A. (2020, Apr 25). Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev, https://doi​.org​/10​.1016​ /j​.cytogfr​.2020​.04​.002 Villapol, S. (2020, Dec). Gastrointestinal symptoms associated with COVID-19: Impact on the gut microbiome. Transl Res, 226, 57–69. https://doi​.org​/10​.1016​/j​.trsl​.2020​ .08​.004 Wang, Y., Li, Y., Zhang, Y., Liu, Y., & Liu, Y. (2022, Mar 7). Are gastrointestinal symptoms associated with higher risk of Mortality in COVID-19 patients? A systematic review and meta-analysis. BMC Gastroenterol, 22(1), 106. https://doi​.org​/10​.1186​/s12876​-022​ -02132-0 Weng, J., Li, Y., Li, J., Shen, L., Zhu, L., Liang, Y., Lin, X., Jiao, N., Cheng, S., Huang, Y., Zou, Y., Yan, G., Zhu, R., & Lan, P. (2021, May). Gastrointestinal sequelae 90 days after discharge for COVID-19. Lancet Gastroenterol Hepatol, 6(5), 344–346. https://doi​ .org​/10​.1016​/S2468​-1253(21)00076-5 Wong, M. C., Huang, J., Lai, C., Ng, R., Chan, F. K. L., & Chan, P. K. S. (2020, Jun 11). Detection of SARS-CoV-2 RNA in fecal specimens of patients with confirmed COVID-19: A meta-analysis. J Infect. https://doi​.org​/10​.1016​/j​.jinf​.2020​.06​.012 Xiao, F., Sun, J., Xu, Y., Li, F., Huang, X., Li, H., Zhao, J., Huang, J., & Zhao, J. (2020, May 18). Infectious SARS-CoV-2 in feces of patient with severe COVID-19. Emerg Infect Dis, 26(8). https://doi​.org​/10​.3201​/eid2608​.200681 Xie, C., Jiang, L., Huang, G., Pu, H., Gong, B., Lin, H., Ma, S., Chen, X., Long, B., Si, G., Yu, H., Jiang, L., Yang, X., Shi, Y., & Yang, Z. (2020, Apr). Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests. Int J Infect Dis, 93, 264–267. https://doi​.org​/10​.1016​/j​.ijid​.2020​.02​.050 Xu, K., Cai, H., Shen, Y., Ni, Q., Chen, Y., Hu, S., Li, J., Wang, H., Yu, L., Huang, H., Qiu, Y., Wei, G., Fang, Q., Zhou, J., Sheng, J., Liang, T., & Li, L. (2020, May 25). [Management of COVID-19: The Zhejiang experience]. Zhejiang Da Xue Xue Bao Yi Xue Ban, 49(2), 147–157. https://www​.ncbi​.nlm​.nih​.gov​/pubmed​/32391658 Yeoh, Y. K., Zuo, T., Lui, G. C., Zhang, F., Liu, Q., Li, A. Y., Chung, A. C., Cheung, C. P., Tso, E. Y., Fung, K. S., Chan, V., Ling, L., Joynt, G., Hui, D. S., Chow, K. M., Ng, S. S. S., Li, T. C., Ng, R. W., Yip, T. C., Wong, G. L., Chan, F. K., Wong, C. K., Chan, P. K., & Ng, S. C. (2021, Apr). Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut, 70(4), 698–706. https://doi​.org​/10​.1136​/gutjnl​-2020​-323020

104  Gastrointestinal Disorders Zabetakis, I., Lordan, R., Norton, C., & Tsoupras, A. (2020, May 19). COVID-19: The inflammation link and the role of nutrition in potential mitigation. Nutrients, 12(5). https://doi​.org​/10​.3390​/nu12051466 Zeng, W., Qi, K., Ye, M., Zheng, L., Liu, X., Hu, S., Zhang, W., Tang, W., Xu, J., Yu, D., & Wei, Y. (2022, Feb 1). Gastrointestinal symptoms are associated with severity of coronavirus disease 2019: A systematic review and meta-analysis. Eur J Gastroenterol Hepatol, 34(2), 168–176. https://doi​.org​/10​.1097​/MEG​.0000000000002072 Zhang, H., Ai, J. W., Yang, W., Zhou, X., He, F., Xie, S., Zeng, W., Li, Y., Yu, Y., Gou, X., Li, Y., Wang, X., Su, H., Xu, T., & Zhang, W. (2020, May 28). Metatranscriptomic characterization of COVID-19 identified a host transcriptional classifier associated with immune signaling. Clin Infect Dis. https://doi​.org​/10​.1093​/cid​/ciaa663 Zhu, T., Jin, J., Chen, M., & Chen, Y. (2022, Dec). The impact of infection with COVID19 on the respiratory microbiome: A narrative review. Virulence, 13(1), 1076–1087. https://doi​.org​/10​.1080​/21505594​.2022​.2090071 Zippi, M., Fiorino, S., Occhigrossi, G., & Hong, W. (2020, Apr 26). Hypertransaminasemia in the course of infection with SARS-CoV-2: Incidence and pathogenetic hypothesis. World J Clin Cases, 8(8), 1385–1390. https://doi​.org​/10​.12998​/wjcc​.v8​.i8​.1385 Zuo, T., Liu, Q., Zhang, F., Lui, G. C., Tso, E. Y., Yeoh, Y. K., Chen, Z., Boon, S. S., Chan, F. K., Chan, P. K., & Ng, S. C. (2021, Feb). Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut, 70(2), 276–284. https://doi​.org​/10​.1136​/gutjnl​-2020​-322294 Zuo, T., Zhan, H., Zhang, F., Liu, Q., Tso, E. Y. K., Lui, G. C. Y., Chen, N., Li, A., Lu, W., Chan, F. K. L., Chan, P. K. S., & Ng, S. C. (2020, Jun 24). Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge. Gastroenterology. https://doi​.org​/10​.1053​/j​.gastro​.2020​.06​.048 Zuo, T., Zhang, F., Lui, G. C. Y., Yeoh, Y. K., Li, A. Y. L., Zhan, H., Wan, Y., Chung, A., Cheung, C. P., Chen, N., Lai, C. K. C., Chen, Z., Tso, E. Y. K., Fung, K. S. C., Chan, V., Ling, L., Joynt, G., Hui, D. S. C., Chan, F. K. L., Chan, P. K. S., & Ng, S. C. (2020, May 19). Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology. https://doi​.org​/10​.1053​/j​.gastro​.2020​.05​.048

7

Metabolic Disorders Charlotte Steenblock, PhD, Nicole Bechmann, PhD, Waldemar Kanczkowski, PhD, Nikolaos Perakakis, MD, and Stefan R. Bornstein, MD

Shortly after the onset of the coronavirus disease 2019 (COVID-19) pandemic in Wuhan, China, in December 2019, it was recognized that COVID-19 displayed a worse prognosis and higher mortality in individuals with comorbidities and in particular those with metabolic dysfunctions (Figure 7.1), such as diabetes, obesity, hypertension, polycystic ovary syndrome, and non-alcoholic fatty liver disease (Steenblock et al., 2021). A metabolic disease is defined as any disease or disorder that disrupts normal metabolism. Most metabolic disorders involve abnormal levels or disturbed function of either enzymes or hormones. Thus, metabolic diseases affect the ability of a cell to perform critical biochemical reactions involving the processing or transport of proteins, carbohydrates, or lipids. Many metabolic disorders are typically inherited single gene anomalies, most of which are autosomal recessive. Several develop later in life and people may appear healthy for many years before symptoms appear. The onset of symptoms usually occurs when the body’s metabolism encounters stress, e.g., after prolonged fasting or during serious illness. In addition to the genetic part, there is a substantial effect of epigenetic factors on the development of metabolic diseases. The economic development in many parts of the world has in the last decades been accompanied by sedentary lifestyles and increasing intakes of energy-dense food leading to non-communicable metabolic diseases. Typically, the pathogenesis begins with obesity, frequently followed by metabolic syndrome, which in turn often results in the development of type 2 diabetes and cardiovascular disease. Although mostly driven by lifestyle, there is still a strong contribution of genetic background in the progression of this syndrome (Holzapfel et al., 2022). The non-communicable metabolic diseases are a global public health problem reaching pandemic levels. According to WHO reports, around 40% of the world population was estimated to be overweight or obese in 2016, and the numbers are still increasing. In 2021, the International Diabetes Federation Diabetes Atlas estimated that around 537 million adults worldwide are living with diabetes. Of these, 5–10% suffer from type 1 diabetes.

DOI: 10.4324/9781003371090-7

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Figure 7.1  People with metabolic diseases have a higher risk of a severe course of COVID19. One possible cause is the chronic low-grade chronic inflammation in the body of these patients. If an infection with SARS-CoV-2 then occurs, there is a high risk of an overreaction of the immune system leading to hyperinflammation and cytokine storm. Furthermore, these people may experience an increased risk of Long COVID.

Metabolic Diseases and COVID-19 A number of reviews and meta-analyses have examined the comorbidities for a severe course of COVID-19. One meta-analysis including 120 worldwide studies concluded that among all COVID-19 cases until July 2020, the most prevalent comorbidities were hypertension (32%), obesity (25%), diabetes (18%), and cardiovascular disease (16%). The mortality for COVID-19 patients with hypertension, diabetes, and obesity was 27–30% (Thakur et al., 2021). Sex differences in the prevalence of metabolic disease may further affect the severity of COVID-19. For example, premenopausal women have a lower prevalence of type 2 diabetes, hypertension, and cardiovascular disease than men of the same age (Bechmann et al., 2022a). On the other hand, females of reproductive age with polycystic ovary syndrome represent a specific subgroup of patients with increased risk for severe COVID-19 (Kyrou et al., 2020; Subramanian et al., 2021) as these patients also have a higher risk of type 2 diabetes, cerebrovascular, and cardiovascular events (Bechmann et al., 2022b).

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Obesity and Acute COVID-19 Obesity and in particular visceral obesity is a risk factor for the development of diabetes, cardiovascular disease, blood hypercoagulability, and vitamin D deficiency, which are high-risk factors for COVID-19 severity (Steenblock, Hassanein, Khan, Yaman, Kamel, Barbir, Lorke, Everett, et al., 2022). Obesity alone is responsible for 20% of COVID-19 hospitalizations, and in combination with type 2 diabetes and hypertension, it is responsible for up to 60% of all COVID-19 hospitalizations (O'Hearn et al., 2021). Several mechanisms might be responsible for the elevated risk for severe COVID-19 and mortality in obese people including amongst others an impaired immune response and changes in the expression of SARS-CoV-2 entry receptors in obese individuals (Sattar et al., 2020; Sudhakar et al., 2022). Furthermore, physical stress on ventilation by obstructing diaphragm excursion as well as the increased risk of pulmonary fibrosis, chronic obstructive pulmonary disorder, and reduced respiratory function in obese patients may contribute to the enhanced severity of COVID-19 in these patients (Ayres, 2020). In humans, the adipose tissue is the largest endocrine organ. In addition to storing energy, the adipose tissue regulates various aspects of metabolism through the secretion of adipocytokines or adipokines, such as adiponectin, leptin, resistin, and visfatin (Tilg & Moschen, 2006). Furthermore, adipose tissue is a source of several proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1, CC-chemokine ligand 2 (CCL2), and plasminogen activator inhibitor type I (PAI-I), and can produce a number of complement factors (Calle & Kaaks, 2004). Many of these factors are pro-inflammatory and induce immune cell infiltration (e.g., macrophages) (Steenblock, Hassanein, Khan, Yaman, Kamel, Barbir, Lorke, Everett, et al., 2022). This cytokine upregulation may lead to the cytokine storm described in acute COVID-19. Both in mice and in humans, it was shown that distinct macrophage populations, M1 and M2, with unique characteristics direct inflammatory versus physiological changes in adipose tissue (Hill et al., 2018). M1 macrophages are typically induced by the pro-inflammatory mediators lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Upon induction, they produce pro-inflammatory cytokines (TNF-α, IL-6, IL-12) and generate reactive oxygen species (ROS), such as nitric oxide (NO), via activation of inducible nitric oxide synthase (iNOS) (Lumeng et al., 2007). M2 macrophages, on the other hand, are induced by anti-inflammatory cytokines, such as IL-4 and IL-13, and are characterized by the secretion of IL-10 and IL-1rα cytokines and limited activity of iNOS (Lumeng et al., 2007). The production of ROS is an important mechanism for resolving infections; however, excessive ROS production can result in tissue damage leading to endothelial dysfunction, increased inflammation, compromised lymphocyte function, and disrupted neurotransmitter assembly (Jensen et al., 2021).

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Obesity is characterized by hyperplasia and hypertrophy of the adipocytes, and the accumulation of macrophages in the adipose tissue may lead to the development of crown-like structures of necrotic adipocytes encircled by macrophages (Russo & Lumeng, 2018). In obesity, a switch from the anti-inflammatory M2 to the pro-inflammatory M1 macrophages is observed (Hornung et al., 2021). On the other hand, it was recently specified that adipose tissueassociated macrophages cannot be completely described by the M1/M2 model with two phenotypic extremes, but rather that the macrophages exist as a whole spectrum (Karlinsey et al., 2022). In patients who died due to COVID-19, a higher prevalence of CD68-positive macrophages in visceral adipose tissue was observed compared to control patients without COVID-19. As expected, these were accompanied by crown-like structures, signs of adipocyte stress, and death (Colleluori et al., 2022). In adipose tissue, diet and obesity have been shown to affect the expression of the entry receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) (Gomez-Zorita et al., 2021). For example, improvements in metabolic health were associated with decreases in soluble ACE2 during weight loss (Cauwenberghs et al., 2021). Yet, it is not known whether a high expression of ACE2 in adipose tissue in relation to SARS-CoV-2 is beneficial or not (Steenblock, Hassanein, Khan, Yaman, Kamel, Barbir, Lorke, Everett, et al., 2022). It has been suggested that adipose tissue could act as a reservoir for SARSCoV-2, thus facilitating virus spread and stimulating the immune response (Ryan & Caplice, 2020). Actually, a recent study did report the presence of SARS-CoV-2 RNA in adipose tissue of both men and women who died due to COVID-19. The virus was found only in adipose tissue of male individuals who were overweight (BMI ≥ 25) or obese (BMI ≥ 30). In women, there was no correlation between BMI and viral load in the adipose tissue (Zickler et al., 2022). In another study, SARS-CoV-2 was present in the adipose of more than 60% of COVID-19 autopsy cases (Poma et al., 2022). The hypothesis of an active persistent SARS-CoV-2 viral reservoir is supported by recent results showing the SARS-CoV-2 spike antigen in the plasma of a majority of Long COVID patients up to 12 months post-diagnosis (Swank et al., 2022).

Diabetes and Acute COVID-19 As described for obesity, chronic subclinical low-grade inflammation often develops in patients with diabetes. This leads to a decrease in anti-inflammatory cytokines and an increase in the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, which mediate insulin resistance (Esser et al., 2014). In severe COVID-19, the inflammatory response to SARS-CoV-2 may further exacerbate insulin resistance and induce endothelial dysfunction (Bornstein et al., 2021). By triggering airway hyper-reactivity, insulin resistance increases the risk of respiratory failure and cardiopulmonary collapse (Santos et al., 2021).

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Patients with COVID-19, without any pre-existing history or diagnosis of diabetes, were demonstrated to have a high occurrence of hyperglycemia (Montefusco et al., 2021). On the other hand, stress hyperglycemia and insulin resistance are also features of other acute critical diseases (Langouche et al., 2021). Therefore, it is still not clear whether insulin resistance is more severe in COVID-19 patients than in non-COVID patients with similar disease severity. The optimal blood glucose level still remains to be defined as patients with uncontrolled or poorly controlled blood glucose levels were demonstrated to experience a worse COVID-19 course than those with normoglycemia (Laurenzi et al., 2021). In single cases, acute COVID-19 was shown to lead to new-onset type 1 diabetes, and in many cases, an infection with SARS-CoV-2 led to an aggravation of prediabetes or pre-existing type 2 diabetes (Steenblock et al., 2021). We and others have shown that pancreatic insulin-producing beta-cells may be infected with SARS-CoV-2, which can cause beta-cell damage and possibly insulin resistance (Steenblock, Hassanein, Khan, Yaman, Kamel, Barbir, Lorke, Rock, et al., 2022). A study from the American Centers for Disease Control and Prevention confirmed these data, as the risk for newly diagnosed diabetes in adolescents was anticipated to be more than doubled when compared to non-infected adolescents or with other respiratory infections (Barrett et al., 2022). Another study with 600,055 people revealed an increased risk of newonset type 2 diabetes after COVID-19. The risk was increased after moderate/ severe COVID-19 compared to patients with mild symptoms. Moreover, the risk was higher than in influenza controls excluding a general predisposition after viral illness (Birabaharan et al., 2022). In addition to hyperglycemia induced by infections, glucocorticoid-induced hyperglycemia is a well-known medical problem. Excessive supplementation of glucocorticoids may lead to insulin resistance associated with increased glucose production and the impaired production and release of insulin from pancreatic beta-cells (Perez et al., 2014). During the corona pandemic, this is a very relevant topic due to long-term treatments with dexamethasone, which may lead to long-lasting metabolic dysregulations (Bornstein et al., 2021).

Non-Alcoholic Fatty Liver Disease and Acute COVID-19 Non-alcoholic fatty liver disease is considered the hepatic manifestation of metabolic syndrome, affecting almost 30% of the general population and demonstrating a continuously increasing prevalence (Riazi et al., 2022). Multiple levels of evidence support the presence of a bidirectional relationship between COVID-19 infection, liver function, and non-alcoholic fatty liver disease (Hoffmann et al., 2022). At the epidemiological level, COVID-19 infection leads very often (up to almost 70%) to an increase in liver transaminases, which indicates hepatocellular damage during acute infection (Hoffmann et al., 2022). Elevated transaminases and bilirubin have been recognized as independent predictors of

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disease severity and especially of admission to intensive care unit as well as to in-hospital mortality (Del Zompo et al., 2020). This increase in transaminases is often transient, albeit cases of hepatic fibrosis or prolonged and severe cholestasis in patients with persisting symptoms compatible with the presence of Long COVID have been reported (Bende et al., 2021). Mechanistically, direct cytotoxic effects by entry of SARS-CoV-2 in hepatocytes, cholangiocytes, and Kupffer cells have been described (Meijnikman et al., 2021; Puelles et al., 2020). Moreover, systemic inflammatory responses commonly observed in COVID-19 may further contribute to hepatic inflammation through the recruitment of immune cells in the liver, as well as by inducing the expression of proinflammatory and procoagulant factors by liver sinusoidal endothelial cells (McConnell et al., 2021). Furthermore, hepatocellular hypoxia due to acute respiratory distress syndrome may increase hepatic lipid accumulation and mitochondrial dysfunction. In combination with venous outflow obstruction and congestion due to cardiac failure, this can induce hepatocyte necrosis (Hoffmann et al., 2022). Finally, medications and especially antibiotics, immune-modulating drugs, antivirals, and corticosteroids may further lead to liver damage (Kulkarni et al., 2020). All the above mechanisms of COVID-19-induced liver damage may even have a greater impact on patients with pre-existing liver diseases, such as non-alcoholic fatty liver disease. Specifically, COVID-19 stimulates de novo lipogenesis by increasing circulating free fatty acids and by activating mTOR signaling as well as by promoting dysbiosis through disruption of the microbiome, which are all considered major contributors of non-alcoholic fatty liver disease development and progression (Hoffmann et al., 2022; Perakakis et al., 2020). Additionally, patients with non-alcoholic fatty liver disease are already in a chronic low-grade inflammatory state, where circulating cytokines are promoting the recruitment of immune cells in the liver, and the cytokine storm often observed in acute COVID-19 may thus build upon this pathologic pre-existing condition. Finally, patients with non-alcoholic fatty liver disease are susceptible to druginduced liver injury, which can further aggravate pre-existing hepatic inflammation (Hoffmann et al., 2022). The presence of non-alcoholic fatty liver disease has been associated with a severe course of COVID-19 infection with 70% higher risk for admission to intensive care unit, as well as with longer viral shedding time (Singh et al., 2021). Several mechanisms may explain this association. First, patients with non-alcoholic fatty liver disease are considered prone to infections, albeit more mechanistic data are needed to support this assumption (Adenote et al., 2021). Second, as mentioned above, patients with non-alcoholic fatty liver disease demonstrate chronically elevated levels of pro-inflammatory cytokines (IL-6, IL-8, TNF) and lower levels of anti-inflammatory cytokines (e.g., IL-10), which can be further aggravated during an acute COVID-19 infection leading possibly to profound and uncontrolled inflammatory responses (Braunersreuther et al., 2012). Furthermore, non-alcoholic fatty liver disease is associated with an increased risk of coagulation due to higher concentrations of factor VIII

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and PAI-1 and lower concentrations of protein C (Tripodi et al., 2014). Thus, the pre-existing pro-coagulant imbalance may contribute to robust activation of coagulation cascades, which is further supported by the positive association between non-alcoholic fatty liver disease and pulmonary thromboembolism observed during COVID-19 infection (Vrsaljko et al., 2022). Finally, patients with non-alcoholic fatty liver disease suffer very often from many comorbidities, such as obesity, diabetes, hyperlipidemia, and hypertension. Thus, they have an increased risk for cardiovascular events during critically ill conditions (Hoffmann et al., 2022). Additionally, they often demonstrate structural or functional abnormalities in the lungs, which make them susceptible to severe pneumonia and respiratory insufficiency.

The Role of Metabolic Diseases in Long COVID An increasing number of studies show metabolic abnormalities, such as dyslipidemia and cardiovascular disease along with signs of abnormal glucose metabolism with insulin resistance and hyperglycemia, and diabetes after infections with SARS-CoV-2 (Pavli et al., 2021; Tabacof et al., 2022). The exact molecular mechanisms behind these symptoms are still not understood but are most likely heterogeneous and might include direct or indirect consequences of the infection with SARS-CoV-2 (Bornstein et al., 2022a). Autoimmunity due to targeting of self-antigens caused by an impairment in the regulatory T cell response or molecular mimicry may be another explanation. An additional proposed mechanism for persisting symptoms is a reactivation of latent viruses in the body (Choutka et al., 2022). In addition, rheological abnormalities, such as blood viscosity and red blood cell deformations, were shown to be caused by COVID-19 infection (Joob & Wiwanitkit, 2021; Kubánková et al., 2021). These different processes are not mutually exclusive and could exist in combination (Choutka et al., 2022). A study from the UK with more than 4,000 patients with COVID-19 who documented their symptoms in a mobile application showed that certain criteria could potentially help to predict whether Long COVID will develop or not. The study showed that in different countries, older people, women, patients with overweight, and COVID-19 patients who were hospitalized had a higher risk of developing Long COVID, regardless of their ethnic background (Sudre et al., 2021). Another study from Norway demonstrated that even patients with mild COVID-19, who had been quarantined at home, often experienced symptoms of Long COVID (Blomberg et al., 2021). In COVID-19 patients, increased circulating levels of glucose and free fatty acids were demonstrated, which could be explained by alterations in carbon homeostasis (Thomas et al., 2020). These increased concentrations of free fatty acids may lead to higher levels of adipokines, myokines, and cytokines. In addition to promoting inflammation, these cytokines may damage the vascular endothelium and activate the renin-angiotensin-aldosterone system, which can lead to increased blood pressure, atherosclerosis, and thrombosis (Vasheghani

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et al., 2022). Indeed, Long COVID symptoms have been associated with endothelium dysfunction (Charfeddine et al., 2021). This was significantly associated with older age, body mass index (BMI), male gender, cardiovascular risk factors, the severity of symptoms during the acute phase of COVID-19 infection, the extension of pulmonary lesions during the COVID-19 infection, and reduced left ventricular global longitudinal strain (Charfeddine et al., 2021). Recent data have shown that COVID-19 leaves a persistent capillary rarefication for up to at least 18 months after the acute infection (Osiaevi et al., 2022). COVID-19 can also increase blood viscosity through the modulation of fibrinogen, albumin, lipoproteins, and red blood cell indices. Increased blood viscosity, with or without abnormal red blood cell function in COVID-19, participates in the reduction of tissue oxygenation with the development of cardio-metabolic complications and Long COVID (Al-Kuraishy et al., 2022). Excessive inflammation and oxidative stress have been considered as main factors leading to fibrosis, thrombosis, autonomic nervous system dysfunction, and autoimmunity, which together result in tissue damage and thus Long COVID (Crook et al., 2021; Vollbracht & Kraft, 2021). On the other hand, oxygen supplementation used to treat patients with severe COVID-19 can lead to increased ROS generation in the mitochondria. This damages mitochondrial complexes and decreases oxidative phosphorylation leading to reduced production of ATP and an elevation in the apoptosis rate. The damage to mitochondria by hyperoxia reduces antiviral reactions and leads to increased tissue damage (Pierce et al., 2022). It has to be noted that besides infection and inflammation as a trigger of metabolic disorders, the administration of steroids, in particular glucocorticoids, may play a role in the development of metabolic disorders in the post-Covid phase. Nearly all patients with a severe course of COVID-19 obtain glucocorticoids in the form of dexamethasone or hydrocortisone, and several patients with long-term damage to the lung parenchyma continue to receive glucocorticoids for an extended period of time (Steenblock, Hassanein, Khan, Yaman, Kamel, Barbir, Lorke, Everett, et al., 2022). Thus, in these patients, steroid-induced metabolic deterioration and steroid-induced diabetes are not surprising. When after extensive use of steroids for several weeks, the administration is abruptly discontinued, it occasionally led to steroid-induced iatrogenic adrenal insufficiency. In the case of poorly controlled and improperly tapered off glucocorticoid therapy, long-term suppression of the hypothalamus-pituitary-adrenal axis is assumed. This can promote symptoms resembling Long COVID, such as extreme fatigue, exhaustion, blood pressure dysregulation, and depression (Kanczkowski et al., 2022; Steenblock, Schwarz, et al., 2022).

Long COVID Consequences for Diabetes Management A significant number of people who died from COVID-19 had pre-existing diabetes with or without obesity and hypertension (Steenblock et al., 2021).

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An increasing number of studies suggest that the same group of patients also bear an increased risk of developing Long COVID. For example, people with type 2 diabetes have a high prevalence of post-Covid fatigue (Su et al., 2022). The manifestation of fatigue syndrome in post-Covid patients with pre-existing diabetes is also associated with reduced muscle strength (Mittal et al., 2021). This reduced muscle strength indicates the presence of sarcopenia, which is more common in patients with poorly controlled diabetes. This shows that in the post-Covid phase, glycemic control and adequate nutritional status are of huge importance. In addition to fatigue, COVID-19 patients with type 2 diabetes and Long COVID experienced weight loss and significantly reduced physical activity. On the other hand, there are also reports of higher food intake and weight gain in patients with Long COVID (Mittal et al., 2021). Yet, another study of hospitalized patients reported no difference between the occurrence of Long COVID symptoms and the presence of diabetes. In this study, it was demonstrated that the role of diabetes is higher in the acute phase of the disease than in the post-Covid phase (Fernandez-de-Las-Penas et al., 2021). Another study reported both acute and long-lasting glycemic disorders in patients after SARS-CoV-2 infection (Montefusco et al., 2021). All in all, long-term metabolic changes must be expected in the post-acute phase of COVID-19 (Sathish et al., 2021) and should consequently be followed up, especially in patients at higher risk. The relationship between COVID19 and the diabetic metabolic state is certainly a mutually reinforcing vicious cycle. On the one hand, the inflammation in acute COVID-19 disease leads to a deterioration in the metabolic situation; on the other hand, diabetes leads to chronic inflammation with alterations in the innate and adaptive immune system, which might be devastating in relation to infection with SARS-CoV-2. Thus, it is not surprising that poorly controlled diabetes has been described as a risk factor for Long COVID (Mrigpuri et al., 2021). These results demonstrate the importance of close monitoring of recovering COVID-19 patients (Khunti et al., 2021).

Vaccine Breakthrough Infections and Re-Infection in Relation to Metabolic Disorders Obesity and other metabolic dysfunctions might favor SARS-CoV-2 vaccine breakthrough infections and thus the development of Long COVID symptoms after the acute phase. A study including fully vaccinated patients with acute COVID-19 admitted to the Yale New Haven Health System hospital revealed that among all pre-existing comorbidities, overweight, type 2 diabetes, and cardiovascular disease were frequently observed in patients with severe or critical illness (Juthani et al., 2021). Another study investigated the effectiveness of COVID-19 vaccination in Scotland. Here, type 2 diabetes, coronary heart disease, and chronic kidney disease were also associated with an increased risk of severe COVID-19 outcomes despite full vaccination (Agrawal et al., 2021). These findings confirm results from Israel demonstrating that the COVID-19

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vaccine effectiveness is slightly lower among people with a higher number of coexisting conditions, such as obesity, type 2 diabetes, and hypertension, when compared to people with less comorbidities (Dagan et al., 2021). These findings are similar to data from patients with obesity and/or type 2 diabetes suffering from immunosenescence and increased HbA1c levels, which were shown to exhibit a reduced immune response to influenza A vaccine (Stefan et al., 2021). Although re-infected individuals usually suffer from a milder form of the disease, a remarkably high proportion of naturally infected or vaccinated individuals were re-infected by new emerging variants. For re-infections, it was reported that in 50% of all cases, at least one of the comorbidities obesity, diabetes, asthma, heart disease, lung disease, and high blood pressure was present (Rahman et al., 2022).

What Can Be Done? Overall, it can be assumed that obesity and poorly controlled diabetes mellitus are not only significant risk factors in the acute phase of COVID-19 and vaccination failure but also for symptoms and complications in Long COVID. Thus, checking and monitoring the metabolic situation must be an integral part of any clinical monitoring of a post-Covid outpatient clinic. Interestingly, many patients with the classic symptoms of Long COVID, including chronic fatigue, report an improvement in their condition after the use of therapeutic apheresis. Apheresis is an extracorporeal method for the removal of selected blood components: either specific cells or specific components of the plasma. There are several types of apheresis mainly based on three physical mechanisms: filtration, precipitation, and adsorption (Julius, 2017; Straube et al., 2019). Exactly how the extracorporeal apheresis procedure could have a positive impact on Long COVID has not yet been fully elucidated. It is clear that after therapeutic apheresis, metabolic parameters, in particular the lipid values, can be significantly improved and reduced by up to 80%. In addition, an anti-inflammatory effect is achieved with a significant reduction in C-reactive proteins and other pro-inflammatory peptides and proteins (Bornstein et al., 2022b; Morawietz et al., 2020). Finally, extracorporeal apheresis achieves a significant reduction in immunoglobulins and autoantibodies. Another effect could be an improvement in blood circulation and the function of the red blood cells, whereby the oxygen content of the blood carriers is also optimized in the brain and the classic symptom reported by patients with Long COVID is improved. Despite promising experiences with several forms of apheresis in the treatment of Long COVID, either alone or in combination with other therapies, such as glucocorticoid treatment and vitamin C, confirmatory data on its efficacy from large well-designed interventional studies are still lacking. A randomized controlled trial is therefore needed and should include a defined patient group with Long COVID syndrome.

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Conclusion Metabolic diseases have become a global challenge, and now combined with the current corona pandemic and Long COVID, the problem has turned out to be devastating. Involving skilled personnel, including diabetologists and endocrinologists in conjunction with general practitioners, in the treatment of these patients is of crucial importance. In addition to the optimal metabolic and endocrine control of the patients, new approaches to nutrition counseling and treatment of these patients have to be considered (Petrie et al., 2021). Furthermore, the importance of preventing obesity as early as childhood has been spotlighted (Saliba & Cuschieri, 2021).

References Adenote, A., Dumic, I., Madrid, C., Barusya, C., Nordstrom, C. W., & Rueda Prada, L. (2021). NAFLD and Infection, a Nuanced Relationship. Canadian Journal of Gastroenterology and Hepatology, 2021, 5556354. Agrawal, U., Katikireddi, S. V., McCowan, C., Mulholland, R. H., Azcoaga-Lorenzo, A., Amele, S., Fagbamigbe, A. F., Vasileiou, E., Grange, Z., Shi, T., Kerr, S., Moore, E., Murray, J. L. K., Shah, S. A., Ritchie, L., O'Reilly, D., Stock, S. J., Beggs, J., Chuter, A., Torabi, F., Akbari, A., Bedston, S., McMenamin, J., Wood, R., Tang, R. S. M., de Lusignan, S., Hobbs, F. D. R., Woolhouse, M., Simpson, C. R., Robertson, C., & Sheikh, A. (2021). COVID-19 hospital admissions and deaths after BNT162b2 and ChAdOx1 nCoV-19 vaccinations in 2.57 million people in Scotland (EAVE II): A prospective cohort study. The Lancet Respiratory Medicine, 9(12), 1439–1449. Al-Kuraishy, H. M., Al-Gareeb, A. I., El-Bouseary, M. M., Sonbol, F. I., & Batiha, G. E. (2022). Hyperviscosity syndrome in COVID-19 and related vaccines: Exploring of uncertainties. Clinical and Experimental Medicine, 1–10. Ayres, J. S. (2020). A metabolic handbook for the COVID-19 pandemic. Nature Metabolism, 2(7), 572–585. Barrett, C. E., Koyama, A. K., Alvarez, P., Chow, W., Lundeen, E. A., Perrine, C. G., Pavkov, M. E., Rolka, D. B., Wiltz, J. L., Bull-Otterson, L., Gray, S., Boehmer, T. K., Gundlapalli, A. V., Siegel, D. A., Kompaniyets, L., Goodman, A. B., Mahon, B. E., Tauxe, R. V., Remley, K., & Saydah, S. (2022). Risk for newly diagnosed diabetes >30 days after SARS-CoV-2 infection among persons aged 200 U/L) was observed in 14.4% of the mild patients (discharged from hospital with no need for invasive ventilation) and in 35.1% of the severe patients (discharged with no need for invasive ventilation). Creatinine (phospho)-kinase levels at admission are higher in patients with COVID who later experience more severe outcomes, and hyperCKemia is associated with a worse prognosis (Orsucci et al., 2021). Rhabdomyolysis (damaged muscle tissue releases its proteins and electrolytes into the blood) and cardiac muscle injury should be assumed when creatinine (phospho)-kinase levels is highly elevated. It has been widely accepted that creatinine-kinase levels more than five times the upper limit of normal (≥1,000 U/L) are diagnostic of rhabdomyolysis (Haroun et al., 2021). Other biomarkers, myoglobin and lactate dehydrogenase, are also elevated in those disease conditions. Biomarker research indicates that muscle injury and subsequent rhabdomyolysis is a characteristic feature of SARS-CoV-2 infection.

Effect of COVID on the Musculoskeletal System of the General Population To prevent the spread of COVID and to enable healthcare systems to manage the increase in seriously ill persons, severe restrictions on daily life were implemented such as home confinement or lockdown. In addition, due to the implementation of strategies to control the COVID infection, training gyms, gymnasiums, and other exercise facilities were closed in many countries,

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depriving people of exercise opportunities. Though such measures were effective to some extent in preventing the spread of COVID, these prolonged practices lead to decreases in regular exercise and deterioration in mental health and quality-of-life. There is substantial evidence supporting the health benefits of physical activity. For example, physical activity can lead to improved perceptions of health in adolescents (Ekelund et al., 2016). There is a curvilinear relationship between physical activity and mortality in older adults (Hupin et al., 2015), and routine physical activity is related to the reduction of the risk of multiple chronic medical conditions (Kyu et al., 2016). Even before the COVID pandemic, most children and adolescents did not reach the physical activity guidelines of 60 min of activity per day recommended by the World Health Organization (Rodriguez-Ayllon et al., 2019). However, the time of physical activity in the children and adolescent population decreased by about 20 min/day (ranging from 10 to 90 min/day) after the COVID pandemic (Rossi et al., 2021). The main determinants of children’s physical activity during the pandemic were age, gender, socioeconomic background, and the outdoor environment (Rossi et al., 2021). A wearable activity tracking software company collected physical activity data from 30 million users in 1 week in March 2020 and found a reduction in the average step counts of up to 40% in most countries compared with the same period the preceding year (Fitbit, 2020). Reductions in physical activity can result in the development of “locomotive syndrome.” Locomotive syndrome is a disease proposed by the Japanese Orthopaedic Association that refers to the decline in mobility due to musculoskeletal weakness/disfunction (Nakamura, 2009, 2011). Locomotive syndrome overlaps with frailty and sarcopenia. However, locomotive syndrome criteria might be useful as the best tool to screen older persons who would be at risk for requiring care in the near future (Ide et al., 2021). In patients with locomotive syndrome, social participation and activities of daily living are often limited, and as the condition progresses, they may have difficulty in living independently and thus require nursing care. Locomotive syndrome is classified into three stages according to the degree of severity: stage 1 (initial decline in mobility function), stage 2 (progressive decline in mobility function), and stage 3 (progressive decline in mobility function and hindered social participation) (Yoshimura et al., 2015). While the prevalence of locomotive syndrome increases secondary to a rapidly aging global population (Kimura et al., 2014), there has been an increasing concern that the magnitude and rapidity of this increase may be greater than expected due to the decrease in physical activity during the COVID pandemic. Especially in the elderly, regular physical activity and/or exercise plays an important role in preventing adverse health outcomes (Garcia-Hermoso et al., 2020; Saint-Maurice et al., 2020). Furthermore, studies have demonstrated that regular exercise is a vital management strategy for better health-related qualityof-life (Chen et al., 2009; Rafferty et al., 2017; Terai et al., 2021b). In Japan, which has a population that is the oldest in the world, the total physical activity

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time per week for the elderly decreased by 26.5% on average from January to April 2020, during the first wave of the COVID pandemic (Yamada et al., 2020). Furthermore, population-based surveys involving 45% of elderly residents revealed that up to 30% had experienced a decrease in regular exercise since the COVID pandemic. Due to this reduction in activity, the elderly showed significant deteriorations of their quality-of-life (Terai et al., 2022b). Regarding locomotive syndrome in the elderly, the prevalence of locomotive syndrome in Japan increased from 41% to 47% within approximately 1.5 years after the COVID outbreak, and 3.1% of the participants demonstrated stage-3 locomotive syndrome (Terai et al., 2022b). Consequently, approximately 2,283,000 elderly individuals have developed locomotive syndrome and 1,122,000 have developed stage-3 locomotive syndrome after the COVID outbreak in Japan. ​ Long COVID is not well understood, but it can be severely disabling to the respiratory, cardiac, renal, endocrine, neurological, and musculoskeletal systems. Although the exact mechanism of Long COVID is still under investigation, Long COVID can be multi-dimensional, spanning symptoms and impairments, activity limitations, and social participation restrictions which all impact people’s functional ability, social and family life, ability to work, and quality-of-life. Dealing with such complexity requires a multidisciplinary approach and patients’ involvement (World Physiotherapy, 2021).

Populations with Musculoskeletal Disease Nearly 35% of patients with musculoskeletal disorders reported a quality-oflife deterioration after the COVID pandemic (Terai et al., 2022a). It is not surprising that quality-of-life decreased after the COVID outbreak, and this was caused by many factors including inaccurate information about virus transmission, limited social support, and financial uneasiness that can increase anxiety (Gunduz et al., 2019; Ikeda et al., 2021; Lardone et al., 2020). However, pain and mobility issues rather than anxiety are the leading causes of decreases in quality-of-life. This could be related to higher levels of chronic pain. Psychological stressors caused by the COVID pandemic could also trigger increases in chronic pain (Clauw et al., 2020).

Current study (n=12,197)

Across Japan (n=36,400,000)

LS (all stages)

765

2,283,000

LS-3

376

1,122,000

Figure 10.1 Estimated number of elderly residents who developed locomotive syndrome after the coronavirus disease 2019 outbreak in Japan (LS, locomotive syndrome; LS-3, locomotive syndrome stage 3).

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The reduced access to and closure of routine clinics have resulted in prolonged waiting times, delays in timely access to medications due to fear of exposure to infection, and financial insecurity (Clauw et al., 2020; Licciardone & Pandya, 2020). One survey revealed that 34% of all patients with musculoskeletal diseases had hesitated before visiting their clinic. These patients may have potentially missed the optimal timing to receive adequate therapy. Up to 35% of patients with musculoskeletal disease reported a decrease in regular exercise after the COVID pandemic. Regular exercise is a vital management strategy for addressing chronic pain (Macfarlane et al., 2017), mental health (De Moor et al., 2006), several chronic diseases (Warburton & Bredin, 2016), life satisfaction (Eek et al., 2021), mortality, (Lee et al., 2012), and quality-oflife (Chen et al., 2009; Rafferty et al., 2017). Additionally, regular exercise is important for improving the symptoms of patients with musculoskeletal disorders (Foster et al., 2018). Maintaining one’s physical activity during times of social restrictions and lockdowns is an important strategy (Chen et al., 2020; Dwyer et al., 2020). However, current guidance cautions against graded exercise therapy for people living with Long COVID, following reports of adverse effects from exercise in people living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A risk-stratification approach to exercise interventions is advocated in Long COVID, with particular focus on the associated risks of exercise with post-exertion malaise and potential cardiac involvement (Brown et al., 2021). Since the treatment of musculoskeletal diseases is often not urgent, many elective surgeries were canceled or postponed during the period when the infection spread (Massey et al., 2020). In fact, one out of three patients were hesitant to go to their clinic (Terai et al., 2021a). In addition to these factors, the psychological stress caused by the COVID pandemic may have contributed to the acceleration of chronic pain (Clauw et al., 2020). Among musculoskeletal disorders, spine and hip/knee joint symptoms were significant risk factors for the development of locomotive syndrome (Terai et al., 2021a). Patients with spinal problems often had difficulty in walking, climbing stairs, and putting on socks while standing on one leg, while most patients with hip/knee complaints had difficulty in climbing stairs.

Prevention of Musculoskeletal System Damage from COVID For recovery following COVID, it is highly important to avoid acute/subacute damage to the musculoskeletal system, especially in elderly people. As mentioned above, muscles are the main target of SARS-CoV-2 infection. The direct effects of COVID like cytokine storms and subsequent inflammatory conditions are often treated by the proper use of medical drugs. Other possible interventions to protect muscles involve exercise, for those who do not have post-exertional malaise, which is a primary symptom of ME/CFS. Multiple studies have reported that resistance exercise can improve muscle size and strength in elderly without any dietary, supplementary, or pharmaceutical

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assistance (Kirwan et al., 2020; Martin Del Campo Cervantes et al., 2019; Stewart et al., 2014). As for the rehabilitation of musculoskeletal diseases and/or locomotive syndrome, locomotion training is reported to be effective, again with the cautions mentioned above for those with ME/CFS. Locomotion training consists of squatting and standing on a single leg with the eyes open, and has been shown to be effective and convenient and can improve physical function in elderly people. In addition to the physical interventions, a psychosocial approach should be used to maintain and encourage adherence, defined as the extent to which subjects – people with locomotive syndrome – follow the recommendations. When a community is in a “lock-down” condition, and individuals are in “self-isolation,” the development and support of home-based exercise is recommended during this COVID pandemic as well as any future pandemics (Aung et al., 2020; Guadalupe-Grau et al., 2020). Telehealth including remote-based exercise, which includes video or online training, has been tried for elderly people in the COVID era as an alternative method of rehabilitation (Hong et al., 2017; Middleton et al., 2020; Vroege et al., 2014). By taking this approach, patients with musculoskeletal disease and/or locomotive syndrome can obtain timely advice for alleviating pain and recognizing critical symptoms which need urgent care. The process of rapidly implementing telehealth services in the context of a changing regulatory landscape and global pandemic has been tried for patients with COVID. For example, telehealth can increase access to specialty care for patients without prolonged travel time compared to in-person visits, and can decrease the socioeconomic burden for both patients and hospital systems (Satin et al., 2020). There are high satisfaction levels with telehealth for both patient and health providers (Greven et al., 2021). However, telehealth has not been widely adopted for musculoskeletal care. This might reflect the inherent limitations of telehealth visits for performing physical examinations and demonstrating rehabilitation instructions, but also reflects the previous restrictions on billing for telehealth visits, and the need for technical troubleshooting during telehealth visits (Piche et al., 2021). There is now a critical ongoing need to develop a system to support telehealth in this COVID-19 era to ensure access to musculoskeletal care.

Case Study of a Patient with COVID A 71-year-old female was comorbid with previous osteoporotic vertebral fractures. Before suffering COVID, she could walk without any assistance and was able to attend functions and engage in activities outside of her home. She showed mild symptoms of COVID such as high fever for 2 or 3 days without any major respiratory problems. She was confined to her home for 10 days after COVID onset by the order of the government. After recovering from COVID, she tried to stay home as much as possible, and reduced activity due to the fear of reinfection. Three months later, when she visited our clinic for a routine check-up, she used a wheelchair and she could not stand alone

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more than few minutes. After a whole-body examination, we found her trunk and lower extremities muscle volume had significantly decreased. We recommended daily exercises with the support of a professional physical trainer. After 6 months of training, she was able to walk with a cane and to go out shopping. This patient recovered her ability to walk in part because her physician pointed out the problem relatively early.

Conclusion During the pandemic, controlling COVID infection is of course a top priority; however, preventing motor impairment and dysfunction is also of importance. It is necessary to develop a treatment strategy for locomotive syndrome compatible with the current pandemic. SPINE20, which is an international advocacy group, appealed to G20 leaders and published a recommendation for the G20 countries to adopt a strategy to promote daily physical activity and exercises among the elderly population to maintain an active and independent life, particularly since the COVID pandemic (Costanzo et al., 2022). To control musculoskeletal symptoms and ensure exercise habits, remote rehabilitation and telemedicine might be needed (Bhuva et al., 2020; Bokolo Anthony, 2020). Physicians, trainers, researchers, healthcare providers, and decision makers in governmental and non-governmental healthcare systems should create guidelines to recommend adequate regular exercise in the post-COVID era. Many have experienced functional loss of muscle strength after COVID. While keeping up activities of daily living as well as exercise to prevent direct and indirect damage to musculoskeletal systems, throughout this chapter, we have mentioned that there are some patients with Long COVID who have experienced post-exertional malaise, and some have been diagnosed with ME/ CFS. For such patients, many will need to learn how to pace themselves and stay within their energy envelopes (Jason et al., 2013 Jason, 2017), and Chapter 2 on fatigue reviews more of these useful recommendations.

References Amato, A. A., & Greenberg, S. A. (2013). Inflammatory myopathies. Continuum, 19(6 Muscle Disease), 1615–1633. https://doi​.org​/10​.1212​/01​.CON​.0000440662​.26427​.bd Areta, J. L., Burke, L. M., Camera, D. M., West, D. W., Crawshay, S., Moore, D. R., Stellingwerff, T., Phillips, S. M., Hawley, J. A., & Coffey, V. G. (2014). Reduced resting skeletal muscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit. Am J Physiol Endocrinol Metab, 306(8), E989–E997. https://doi​.org​/10​.1152​/ajpendo​.00590​.2013 Aung, M. N., Yuasa, M., Koyanagi, Y., Aung, T. N. N., Moolphate, S., Matsumoto, H., & Yoshioka, T. (2020). Sustainable health promotion for the seniors during COVID-19 outbreak: A lesson from Tokyo. J Infect Dev Ctries, 14(4), 328–331. https://doi​.org​/10​ .3855​/jidc​.12684 Authier, F. J., Chazaud, B., Plonquet, A., Eliezer-Vanerot, M. C., Poron, F., Belec, L., Barlovatz-Meimon, G., & Gherardi, R. K. (1999). Differential expression of the IL-1

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and step intensity with mortality among US adults. JAMA, 323(12), 1151–1160. https:// doi​.org​/10​.1001​/jama​.2020​.1382 Satin, A. M., Shenoy, K., Sheha, E. D., Basques, B., Schroeder, G. D., Vaccaro, A. R., Lieberman, I. H., Guyer, R. D., & Derman, P. B. (2020). Spine patient satisfaction with telemedicine during the COVID-19 pandemic: A cross-sectional study. Global Spine J, 2192568220965521. https://doi​.org​/10​.1177​/2192568220965521 Stewart, V. H., Saunders, D. H., & Greig, C. A. (2014). Responsiveness of muscle size and strength to physical training in very elderly people: A systematic review. Scand J Med Sci Sports, 24(1), e1–10. https://doi​.org​/10​.1111​/sms​.12123 Taniguchi, M., Ikezoe, T., Tsuboyama, T., Tabara, Y., Matsuda, F., Ichihashi, N., & Nagahama Study g. (2021). Prevalence and physical characteristics of locomotive syndrome stages as classified by the new criteria 2020 in older Japanese people: Results from the Nagahama study. BMC Geriatr, 21(1), 489. https://doi​.org​/10​.1186​/s12877​-021​-02440-2 Tay, M. Z., Poh, C. M., Renia, L., MacAry, P. A., & Ng, L. F. P. (2020). The trinity of COVID-19: Immunity, inflammation and intervention. Nat Rev Immunol, 20(6), 363– 374. https://doi​.org​/10​.1038​/s41577​-020​-0311-8 Terai, H., Hori, Y., Takahashi, S., Tamai, K., Iwamae, M., Hoshino, M., Ohyama, S., Yabu, A., & Nakamura, H. (2021a). Impact of the COVID-19 pandemic on the development of locomotive syndrome. J Orthop Surg, 29(3), 23094990211060967. https://doi​.org​/10​ .1177​/23094990211060967 Terai, H., Tamai, K., Takahashi, S., Hori, Y., Iwamae, M., Ohyama, S., Yabu, A., Hoshino, M., & Nakamura, H. (2021b). The health-related quality of life of patients with musculoskeletal disorders after the COVID-19 pandemic. Int Orthop. https://doi​ .org​/10​.1007​/s00264​-021​-05256-2 Terai, H., Tamai, K., Takahashi, S., Hori, Y., Iwamae, M., Ohyama, S., Yabu, A., Hoshino, M., & Nakamura, H. (2022a). The health-related quality of life of patients with musculoskeletal disorders after the COVID-19 pandemic. Int Orthop, 46(2), 189– 195. https://doi​.org​/10​.1007​/s00264​-021​-05256-2 Terai, H., Tamai, K., Takahashi, S., Katsuda, H., Shimada, N., Hori, Y., Kobayashi, Y., & Nakamura, H. (2022b). Development of locomotive syndrome in elderly population after COVID-19 outbreak: A population-based cross-sectional study with over 12,000 participants. J Orthop Sci. https://doi​.org​/10​.1016​/j​.jos​.2022​.05​.012 Ufuk, F., Demirci, M., Sagtas, E., Akbudak, I. H., Ugurlu, E., & Sari, T. (2020). The prognostic value of pneumonia severity score and pectoralis muscle Area on chest CT in adult COVID-19 patients. Eur J Radiol, 131, 109271. https://doi​.org​/10​.1016​/j​.ejrad​ .2020​.109271 Vroege, D. P., Wijsman, C. A., Broekhuizen, K., de Craen, A. J., van Heemst, D., van der Ouderaa, F. J., van Mechelen, W., Slagboom, P. E., Catt, M., Westendorp, R. G., Verhagen, E. A., & Mooijaart, S. P. (2014). Dose-response effects of a Web-based physical activity program on body composition and metabolic health in inactive older adults: Additional analyses of a randomized controlled trial. J Med Internet Res, 16(12), e265. https://doi​.org​/10​.2196​/jmir​.3643 World Physiotherapy. (2021). World Physiotherapy Response to COVID-19 Briefing Paper 9. Safe Rehabilitation Approaches for People Living with Long COVID: Physical Activity and Exercise. London, UK: World Physiotherapy. https://world​.physio​/sites​/default​/files​ /2021​-07​/Briefing​-Paper​-9​-Long​-Covid​-FINAL​-English​-2021​_0​.pdf Warburton, D. E., & Bredin, S. S. (2016). Reflections on physical activity and health: What should we recommend? Can J Cardiol, 32(4), 495–504. https://doi​.org​/10​.1016​/j​.cjca​ .2016​.01​.024

178  Musculoskeletal Disorders Welch, C., Greig, C., Masud, T., Wilson, D., & Jackson, T. A. (2020). COVID-19 and acute sarcopenia. Aging Dis, 11(6), 1345–1351. https://doi​.org​/10​.14336​/AD​.2020​ .1014 Wierdsma, N. J., Kruizenga, H. M., Konings, L. A., Krebbers, D., Jorissen, J. R., Joosten, M. I., van Aken, L. H., Tan, F. M., van Bodegraven, A. A., Soeters, M. R., & Weijs, P. J. (2021). Poor nutritional status, risk of sarcopenia and nutrition related complaints are prevalent in COVID-19 patients during and after hospital admission. Clin Nutr ESPEN, 43, 369–376. https://doi​.org​/10​.1016​/j​.clnesp​.2021​.03​.021 Yamada, M., Kimura, Y., Ishiyama, D., Otobe, Y., Suzuki, M., Koyama, S., Kikuchi, T., Kusumi, H., & Arai, H. (2020). Effect of the COVID-19 epidemic on physical activity in community-dwelling older adults in Japan: A cross-sectional online survey. J Nutr Health Aging, 24(9), 948–950. https://doi​.org​/10​.1007​/s12603​-020​-1424-2 Yoshimura, N., Muraki, S., Oka, H., Tanaka, S., Ogata, T., Kawaguchi, H., Akune, T., & Nakamura, K. (2015a). Association between new indices in the locomotive syndrome risk test and decline in mobility: Third survey of the ROAD study. J Orthop Sci, 20(5), 896–905. https://doi​.org​/10​.1007​/s00776​-015​-0741-5 Yoshimura, N., Muraki, S., Oka, H., Tanaka, S., Ogata, T., Kawaguchi, H., Akune, T., & Nakamura, K. (2015b). Association between new indices in the locomotive syndrome risk test and decline in mobility: Third survey of the ROAD study. J Orthop Sci, 20(5), 896–905. https://doi​.org​/10​.1007​/s00776​-015​-0741-5 Zhao, X., Li, Y., Ge, Y., Shi, Y., Lv, P., Zhang, J., Fu, G., Zhou, Y., Jiang, K., Lin, N., Bai, T., Jin, R., Wu, Y., Yang, X., & Li, X. (2021). Evaluation of nutrition risk and its association with mortality risk in severely and critically ill COVID-19 patients. JPEN J Parenter Enteral Nutr, 45(1), 32–42. https://doi​.org​/10​.1002​/jpen​.1953 Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G. F., Tan, W., China Novel Coronavirus, I., & Research, T. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med, 382(8), 727–733. https://doi​.org​/10​ .1056​/NEJMoa2001017

11 Mental Health Disorders Yochai Re’em, MD, and Karanbir Padda, MD

A historical lens is crucial to understanding the mental health ramifications of COVID-19. Documented mental health consequences of previous pandemics and natural disasters include anxiety disorders, mood disorders, substance use disorders, trauma or stress-related disorders, and others (Esterwood & Saeed, 2020). The influenza pandemics of 1889/1892 (Russian flu), the Spanish flu (1918–1919), and diphtheria have had neuropsychiatric consequences (Stefano, 2021). A systematic review and meta-analysis of prevalence estimates of acute, ongoing, and post-acute mental health sequelae of SARS-CoV-1, SARSCoV-2, MERS-CoV, and Ebola found rates of all mental health sequelae to be similar among viruses (Zürcher et al., 2022). Both biological and psychosocial factors, direct and indirect, may contribute to mental health consequences in SARS-CoV-2 infection. This chapter will outline the theoretical pathophysiology, epidemiology, and approach to the evaluation and treatment of mental illness following COVID-19 illness. It includes treatment considerations for mood disorders, anxiety disorders, psychotic disorders, traumatic and stress-related disorders, and special considerations regarding somatic symptom disorders. Data on the treatment of psychiatric disorders in COVID-19 and Long COVID is limited. Existing evidence on the treatment of comorbid psychiatric conditions in disease entities that are found in high rates in the Long COVID population, including ME/CFS and dysautonomias, offers significant value.

Pathophysiology Current understanding of the pathophysiologic mechanisms in Long COVID includes a dysregulated immune system, direct virus-mediated end-organ damage, autonomic nervous system damage, autoimmunity, endothelial dysfunction and hypercoagulability, and viral persistence (Castanares-Zapatero et al., 2022). However, there exists little data on pathophysiologic understanding of the neuropsychiatric outcomes of COVID-19 infection. Mental health conditions in Long COVID may be related to a combination of neuro-immune and inflammatory repercussions of viral infection, direct effects of viral infection DOI: 10.4324/9781003371090-11

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on the central nervous system, microthrombosis, and psychological aspects of the illness. While there is evidence that SARS-CoV-2 invades the olfactory mucosa, as well as evidence that it could pass through the blood-brain barrier (Zhang et al., 2021), definitive clinical evidence of large-scale brain invasion is limited. As a result, current understanding is that long-term neuropsychiatric effects are likely related to neuroinflammation and hypoxic injury, along with a potential for brain stem involvement (Boldrini et al., 2021). Tumor necrosis factor-α has been established as a major component of the SARS-CoV-2 immune response, with additional components including interleukins, complement proteins, and quinolinic acid, which can increase glutamate and upregulate N-methyl-Daspartate receptors (Boldrini et al., 2021). Additionally, inflammation is associated with anhedonia, depression, fatigue, and suicidal behavior (Roman & Irwin, 2020). While many studies show robust evidence of increased peripheral inflammatory markers in depression, cerebrospinal fluid levels of C-reactive protein, tumor necrosis factor-α, and interleukin-6 in particular have been linked to anhedonia and depression (Roman & Irwin, 2020). Thus, peripheral- and neuro-inflammation are proposed mechanisms of depression in Long COVID. Additionally, evidence of microthrombi in the central nervous system in COVID-19 has suggested a combination of microstrokes, neuronal damage, and proinflammatory status, similar to the mechanism of neuropsychiatric conditions in traumatic brain injury (Boldrini et al., 2021). There exists limited data exploring these theories in COVID-19. One study found that the severity of post-COVID depression has been associated with a higher systemic immune-inflammation index, which represents alterations to peripheral platelet, neutrophil, and lymphocyte counts (Mazza et al., 2020). These authors further identified this association at 1 and 3 months followup, with cytokine-modulating agents in the acute period appearing protective against development of depressive symptoms post-COVID (Benedetti, Mazza, et al., 2021). COVID-19 viral antigen has been identified in cerebrospinal fluid, and correlates with central nervous system immune markers, neuroaxonal injury, and the presence of long-term neurologic sequelae (Edén et al., 2022). Antineural autoantibodies and anti-SARS-CoV-2 IgG have been described in teenagers with post-COVID neuropsychiatric symptoms, including psychosis and anxiety (Bartley et al., 2021). Therefore, immune alterations and inflammatory aspects appear important when considering the psychiatric consequences of COVID-19 illness, while other potential contributors remain unexplored.

Approach to Evaluation and Treatment The approach to the evaluation and treatment of mental health conditions in Long COVID can be guided by experience in ME/CFS (Goldberg et al., 2022). Psychiatric providers should work in a multidisciplinary team, ensuring that symptoms are representative of a comorbid psychiatric condition or psychological

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distress, and that reversible medical causes of psychiatric disease are ruled out. This may require liaising with specialists to ensure an adequate workup. Long COVID patients describe encountering stigma, dismissal, and skepticism from medical providers (Pantelic & Alwan, 2021). As a result, many arrive at psychiatric evaluation having heard from other providers that their symptoms are psychosomatic and/or unlikely to benefit from continued medical workup. Fractured relationships between patients and providers are a result of several factors. Patients experience frustration in their quest for treatment and recovery, while providers experience feelings of inadequacy, resentment, and anger at patients perceived as manipulating treatment (Edwards et al., 2010). Mental health consultants may find themselves then in a position where they are forced to choose a position in the split. Approaches to navigating this split may include educating medical providers about emerging research findings relating to Long COVID, facilitating understanding that Long COVID is not a primary psychiatric condition nor the direct result of psychological factors, and providing support to patients who are struggling with an illness that has limited evidence-based treatments available. Mental health clinicians should be clear and direct in defining their goal within the multidisciplinary treatment team, emphasizing that psychiatric and psychological intervention has not been shown to be effective at curing non-psychiatric symptoms. Instead, a helpful focus can be on the treatment of comorbid psychiatric conditions and psychological symptoms when present, and/or providing psychological support and guidance. Traditional psychiatric screening measures such as the Beck Depression Inventory (Brown, Kaplan, & Jason, 2012) rely on somatic symptoms, such that they should be interpreted with caution in patients who are at a higher baseline of somatic symptoms compared to the rest of the population. Screening tools assess fatigue, change in appetite, weight loss or weight gain, challenges with concentration, and more, all of which may be impacted in Long COVID in the absence of comorbid psychiatric disease. Providers should delineate between somatic symptoms that may be part of a psychiatric condition as opposed to those that are not. Evidence in ME/CFS shows the rates of psychiatric comorbidity vary significantly by diagnostic instrument used (Taylor & Jason, 1998), and ME/CFS can be differentiated from depression by focusing on how often individuals experience fatigue, along with the severity of post-exertional malaise, unrefreshing sleep, confusion-disorientation, and shortness of breath (Hawk, Jason, & Torres-Harding, 2006). Anhedonia, guilt, and amotivation are not expected to be seen in ME/CFS, dysautonomia, or Long COVID in the absence of psychiatric comorbidity. Additionally, ME/ CFS symptoms may worsen in the afternoon, while in depressive disorders symptoms tend to improve over the course of the day. In ME/CFS, exercise and exertion worsen symptoms, while these improve symptoms in depressive disorders, and ME/CFS patients typically want to be active but cannot, while those with depressive spectrum disorders do not have this desire (Friedberg et al., 2012).

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Much of the approach to treatment in ME/CFS can be utilized in the Long COVID population. In particular, the goals of treatment are symptom reduction and quality of life improvement, with wide variability that ranges from significant decompensation to substantial improvement (Friedberg et al., 2012). Additionally, support includes acknowledgment that normal diagnostic test findings do not negate the existence of an illness that has the potential to result in significant disturbance to one’s functioning (Friedberg et al., 2012). Finally, the use of medications should be approached with care, as those with ME/CFS may poorly tolerate medications in higher numbers than the general population; as a result, clinicians are advised to start at very low doses and escalate dose slowly with caution (Friedberg et al., 2012).

Mood Disorders The prevalence of depression following COVID-19 ranges widely in studies, from 20 to 53%, in part due to differences in follow-up period, sample, characteristics, severity of illness and illness course, and screening tools (Deng et al., 2021). A 2021 retrospective cohort study found 6-month post-COVID rates of a mood disorder to be 13.7%, and of a first-lifetime mood disorder to be 4.2%, both of which were higher than those in influenza and other respiratory tract infections (Taquet et al., 2021). Meanwhile, a 2-year retrospective cohort study identified the risk of mood disorders returning to baseline after 43 days, reaching an equal overall incidence to the matched comparison group at 457 days (Taquet et al., 2022). A review identified female gender and severity of COVID-19 illness as contributors to depressive symptoms post-COVID, with additional factors including lack of social support, isolation, low or high levels of education, and exposure to media (Dong et al., 2021; Mazza, Palladini, et al., 2022). Inflammatory markers including C-reactive protein, interleukin-1-β, cortisol, systemic inflammation index, neutrophil count, interleukin-6, and T-cell ratios have been found to be associated with post-COVID depressive symptoms (Mazza, Palladini, et al., 2022). The treatment of depression in Long COVID is guided by limited literature in post-COVID depression, existing literature on the use of antidepressants in ME/CFS, and special considerations relating to specifics of the SARS-CoV-2 virus. One study assessed 60 patients with major depressive episodes within 6 months following COVID-19 illness, finding that 55/60 responded to a selective serotonin reuptake inhibitor, with a mean reduction in Hamilton Depression Rating Scale of 16.7 at 4 weeks of treatment. Antidepressants utilized in this study included sertraline, citalopram, paroxetine, fluvoxamine, and fluoxetine. However, this study excluded individuals who had been taking an antidepressant in the 3 months prior to admission, and also excluded those with major medical and neurological disorders (Mazza, Zanardi, et al., 2022). A poster presented at the European College of Neuropsychopharmacology Congress in 2021 evaluated escitalopram in

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33 patients with depression after COVID-19, finding a mean decrease in Hamilton Depression Rating Scale of 9.8 after 10 weeks of treatment (Chaban et al., 2021). A case report of a 58-year-old man with post-COVID depression and anxiety explored the utility of transcranial direct current stimulation, finding a reduction in Hamilton Depression Rating Scale of 20 after 20 days of once-daily transcranial direct current stimulation sessions (Gómez et al., 2021). A case report utilizing famotidine found improved emotional reactivity, amotivation, and poor attention, with a decrease in Beck Depression Inventory (Alper, 2020). Pending further evidence of antidepressant use in post-COVID depression, data on antidepressant use in ME/CFS can be helpful. The data on the use of antidepressants in ME/CFS largely comes from failed efforts to improve fatigue and other non-psychiatric symptoms but shows some promise for treating comorbid depressive disorders. Studies showing some efficacy in improving depression scales included a variety of tricyclic and tetracyclic antidepressants, including nortriptyline, maprotiline, amitriptyline, and doxepin, as well as selective serotonin reuptake inhibitors such as escitalopram, monoamine oxidase inhibitors such as meclobomide, and bupropion (Pae et al., 2009). Those patients who have a dysautonomia such as postural orthostatic tachycardia syndrome have alterations in sympathetic activity. Serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants can increase cardiac sympathetic control and decrease vagal activity, worsening tachycardia (Licht et al., 2012), while selective serotonin reuptake inhibitors can cause peripheral vasoconstriction, decreasing venous pooling, which may benefit those with dysautonomias such as postural orthostatic tachycardia syndrome (Miller & Raj, 2018). There are several unique pathophysiologic factors to Long COVID that may make some antidepressants preferable. SSRIs decrease serotonin levels in platelets and thereby decrease platelet aggregation and prolong bleeding time (Halperin & Reber, 2007), which may be of clinical relevance when considering the microclot theory of Long COVID. Mast cell dysfunction in Long COVID (Proal & VanElzakker, 2021) may be minimized by SSRIs that suppress mast cell function (Haque & Ryan, 2018). Sigma-1-receptor agonism can regulate inflammation and reduce platelet aggregation (Brimson et al., 2021; Sukhatme et al., 2021). Fluvoxamine, the SSRI with the highest sigma-1 affinity (Albayrak & Hashimoto, 2017), has shown promise in decreasing the risk of hospitalization and clinical deterioration in high-risk COVID-19 outpatients (Lenze et al., 2020). Known side effects of antidepressants (Lam et al., 2009) can be utilized clinically in the context of a whole picture of the patient’s Long COVID symptoms, minimizing the use of antidepressants that may worsen existing symptoms, and prioritizing those agents that may help by counteracting existing symptoms. Finally, pharmacologic agents for mood disorders should consider the underlying status of end-organ function, as COVID-19 has been associated with disrupted renal function (Nugent et al., 2021) and liver injury (Li et al., 2022), among other issues.

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In addition to depressive episodes, manic episodes are a known consequence of viral infections, and have been documented in relation to flu, neurosyphilis, HIV encephalopathy, and others (Russo et al., 2022). A review assessing postCOVID mania found 23 patients with first manic episode following infection, with mean age of 44, 4 of whom had a prior psychiatric history (Russo et al., 2022). Successful treatments in these cases included atypical and typical antipsychotics, benzodiazepines, and mood stabilizers (Russo et al., 2022).

Anxiety Disorders Anxiety is one of the most common neuropsychiatric sequelae of COVID-19 illness, with a meta-analysis showing a pooled prevalence of 47% (Deng et al., 2021). The reported prevalence of anxiety disorders following COVID-19 illness varies for similar reasons to those discussed in the mood disorders section. One recent study reported the rate of generalized anxiety disorder was 59.3% in COVID-19 survivors compared to 34.6% in controls (Korkut, 2022). In addition to generalized anxiety, obsessive compulsive disorder symptoms have been reported, with one study finding that 20% of patients suffered from obsessive compulsive disorder following COVID-19 illness, and another study suggesting signs of obsessive compulsive disorder improved from 1 to 3 months follow-up (Mazza et al., 2020, 2021). Female gender, previous psychiatric history, baseline medical comorbidities, and COVID-19 disease severity are suggested in several studies to be risk factors for post-COVID anxiety (Schou et al., 2021). Baseline systemic immune-inflammation index is also positively associated with anxiety scores at follow-up (Mazza et al., 2020). Literature regarding the treatment of post-COVID anxiety disorders is limited. The case report utilizing transcranial direct current stimulation, discussed above in reference to depression, also found a reduction in Hamilton Anxiety Rating Scale of 24 points (Gómez et al., 2021). The case report utilizing famotidine also found a reduction in Beck Anxiety Inventory (BAI) scores (Alper, 2020). There are no known pharmacologic studies specifically evaluating the treatment of anxiety disorders post-COVID, with the current literature largely extrapolating from the treatment of anxiety disorders in the medically ill population (Nakamura et al., 2021). The first-line long-term treatment of anxiety disorders is selective serotonin reuptake inhibitors. For the acute management of anxiety, considerations may include benzodiazepines, hydroxyzine, gabapentin, and buspirone. Low-dose benzodiazepine can be helpful for anxiety and insomnia in ME/CFS, and aid in the treatment of comorbid restless leg syndrome (Carruthers et al., 2003). However, for those with comorbid posttraumatic stress disorder, the use of benzodiazepine is known to worsen the overall severity of posttraumatic stress disorder in the long term (Guina et al., 2015). Further, benzodiazepines impair anterograde memory (LeQuang, 2021), which has been described as a component of cognitive dysfunction in Long COVID (Davis et al., 2021). Hydroxyzine can be used given its low anticholinergic burden, though its status as a histamine H1-antagonist means it

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can worsen fatigue and cognitive dysfunction, albeit less so than a benzodiazepine (De Brabander & Deberdt, 1990). Gabapentin has efficacy for neuropathic pain and may improve energy, anxiety, and depression in ME/CFS (Goldstein, 2013). However, it also carries a risk of dependence, and is associated with cognitive dysfunction (Shem et al., 2018). Buspirone is non-sedating, does not lead to tolerance or dependence, and has been used for anxiety in ME/ CFS (Carruthers et al., 2003). However, it may worsen headaches, dizziness, and lightheadedness, and has been shown to induce more nausea, with higher prolactin levels in ME/CFS compared to controls (Sharpe et al., 1996). Thus, like the approach for antidepressants, anxiolytics should be selected with caution based upon comorbidities and the spectrum of Long COVID symptoms present.

Psychotic Disorders New-onset post-COVID psychosis has frequently been reported in the literature. A large retrospective cohort study found an increased risk of new onset psychosis in patients with COVID-19 infection, as well as an increased incident diagnosis of psychotic disorders at 6 month follow-up compared to influenza infection (Taquet et al., 2021). In another systematic review, post-COVID psychosis was reported more frequently in males, though comorbidities for mental illness, substance use, and medical conditions were not consistently reported. The most reported psychotic symptoms were delusions (93%), followed by hallucinations (69%). Auditory hallucinations were the most common form of hallucination (60%). Mood symptoms were also reported, with mania in 17% of patients and depression in 8% of patients. The duration of psychiatric symptoms ranged from 2 to 90 days (Smith et al., 2021). The extent to which SARS-CoV-2 possesses a unique biological mechanism that specifically predisposes infected individuals to psychosis is difficult to determine. There are confounding factors in some reported cases of postCOVID psychosis. These include psychosis occurring as a constellation of a broader delirium in COVID-19 infection; being induced by substance use or medications known to induce psychosis; and non-psychiatric factors, including psychological stress, isolation, and uncertainty (Watson et al., 2021). Proposed pathophysiologic mechanisms of post-COVID psychosis include direct viral-mediated neuroinvasion and a systemic inflammatory response. One case report of a patient with new onset mania and psychosis post-COVID found SARS-CoV-2 immunoglobulin G to be positive in cerebrospinal fluid (Lu et al., 2020). Regarding the inflammatory hypothesis of post-COVID psychosis, activated microglia release inflammatory cytokines, increasing levels of available glutamate, which over-activates N-methyl-D-aspartate receptors, and thereby impacts cognition and potentially leads to psychotic symptoms (Russo et al., 2022; Schou et al., 2021). There is limited literature to guide the treatment of post-COVID psychosis. In the evaluation of post-COVID psychosis, processes such as delirium,

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autoimmune encephalitis, and substance-induced psychosis should be ruled out. Patients with post-COVID psychosis may require psychiatric hospitalization. A systematic review of 57 patients with post-COVID psychosis found that 72% demonstrated significant improvement or resolution of symptoms, while 8.8% had resolution of psychosis with residual anxiety, depression, speech latency, and psychomotor retardation (Chaudhary et al., 2022). The primary pharmacologic treatment of post-COVID psychosis is antipsychotic medication. Addition of a benzodiazepine may be considered for comorbid anxiety, insomnia, agitation, and catatonia. Doses used and the duration of required treatment vary. The treatment success of antipsychotics in post-COVID psychosis may be partially related to their immunomodulatory effects. Various second-generation antipsychotics have documented antiinflammatory effects (Jansen van Vuren et al., 2021). Aripiprazole, risperidone, and olanzapine specifically have been found to be more efficient in lowering specific cytokines known to be elevated in COVID-19 patients (Capuzzi et al., 2017). Aripiprazole also modulates the expression of immunomodulatory genes shown to be altered in COVID-19 patients and has been hypothesized as treatment for acute COVID-19 infection (Crespo-Facorro et al., 2021). An additional potential advantage of aripiprazole is that it may improve other post-COVID symptoms such as fatigue, brain fog, unrefreshing sleep, and post-exertional malaise, with a small study showing positive effects in these symptoms in patients with ME/CFS (Crosby et al., 2021). Of the first generation antipsychotics, chlorpromazine has been hypothesized to have possible advantages in post-COVID psychosis given its varying immunomodulatory and antiviral effects (Muric et al., 2020). Chlorpromazine also has high affinity for sigma-1-receptor, which regulates inflammation and platelet aggregation, and is a proposed mechanism for reducing severity and clinical deterioration in acute COVID-19 illness (Brimson et al., 2021; Lenze et al., 2020). Comorbid or residual mood symptoms may require treatment with an antidepressant or mood stabilizer. Patients with treatment-resistant post-COVID psychosis may require electroconvulsive therapy, with three cases of post-COVID psychosis showing favorable effects of electroconvulsive therapy (Chaudhary et al., 2022).

Trauma and Stressor-Related Disorders The Diagnostic and Statistical Manual of Mental Disorders-5 designates a medical illness as a traumatic event only if it is “sudden and catastrophic” (American Psychiatric Association, 2022). In practice, there is literature describing posttraumatic stress disorder as a result of a variety of medical conditions, including myocardial infarction and cancer (Roy-Byrne & Stein, 2018). Of importance to Long COVID, the observation that mild traumatic brain injury has been associated with posttraumatic stress disorder (Bryan et al., 2013) raises concern that neurobiological effects of Long COVID, which may be similar to those seen in traumatic brain injury, can increase the risk of posttraumatic stress

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disorder. From a biological perspective, there is a suggestion that posttraumatic stress disorder may be considered in part an endothelial disease given its association with cardiovascular effects (Grenon et al., 2016). This may be of special relevance to Long COVID given the endothelial dysfunction theories of COVID-19 illness. Additionally, there is evidence that increased blood-brain barrier permeability can result in the extravasation of stress molecules such as angiotensin II, endothelin-1, and plasminogen activator inhibitor 1, causing amygdala, hippocampal, and medial prefrontal cortex activation, thereby increasing the likelihood of stress reactions (Sfera et al., 2021). Posttraumatic stress symptoms/disorder are well established consequences of other infectious conditions such as SARS-1 and MERS (Rogers et al., 2020). Generally, intensive care unit survivors are known to have a prevalence of posttraumatic stress disorder of around 34% at 7–12 months post-intensive care unit for all conditions (Parker et al., 2015). While historically severe illness has been associated with higher rates of posttraumatic stress disorder, those with less severe COVID-19 illness have also been observed to have significant rates of posttraumatic stress symptoms (Badenoch et al., 2020). Importantly, those with posttraumatic stress symptoms that do not meet criteria for the disorder still experience functional limitations due to their symptoms (Shalev et al., 2017). Factors associated with posttraumatic stress symptoms/disorder following COVID-19 illness include younger age, female gender, intensive care unit stay, and a positive psychiatric history (Nakamura et al., 2021). Interestingly, a study in China found hospitalization to be protective for posttraumatic stress disorder, compared to those treated in the emergency room and discharged (Yang et al., 2020). In a study evaluating posttraumatic stress symptoms in hospitalized COVID-19 patients in China, the posttraumatic stress disorder checklist for DSM-5 was significantly higher in those with COVID-19, also finding that left hippocampal and amygdala volumes were negatively correlated with the checklist score in the COVID-19 survivors (Tu et al., 2021). There are no studies evaluating the pharmacological treatment of posttraumatic stress symptoms/disorder as a result of COVID-19 illness. Selective serotonin reuptake inhibitors and the serotonin/norepinephrine reuptake inhibitor venlafaxine both have evidence for use in posttraumatic stress disorder, while tricyclic antidepressants and monoamine oxidase inhibitors are considered second or third line, with some evidence for imipramine and phenelzine (Ravindran & Stein, 2009).

Psychotherapies Psychotherapies utilized in those with psychiatric conditions in Long COVID are aimed at reducing the burden of psychological symptoms to increase overall functioning. They cannot be expected to meaningfully impact those symptoms that are not directly caused by a comorbid psychiatric condition or psychological distress. For this reason, close attention to the differential as discussed above should ensure that the goals of the psychotherapy are adequate.

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In general, supportive therapies have shown to be effective in treating individuals with medical illness ranging from irritable bowel syndrome to coronary artery disease, cancers, and chronic pain, significantly reducing morbidity and length of stay (Welton & Crocker, 2021). Tenets of this treatment include helping patients identify and tolerate their emotions, develop a realistic healthy narrative about their condition, cope with external stresses, and engage support systems (Welton & Crocker, 2021). Of note, a “realistic healthy narrative” about Long COVID may be challenging, and therefore may need to be deemphasized as a goal, as the disease is in its infancy and there exist few reliable predictors of long-term trajectory. In conjunction with a supportive stance, a self-psychological psychoanalytically informed perspective can aid in exploring conflicts and challenges such as grief and loss as they relate to chronic illness (Garrett & Weisman, 2001). Few studies have explored the role for psychotherapies in treating postCOVID psychiatric and psychological conditions, though cognitive behavioral therapy remains the most studied. To address anxiety, one randomized control trial compared a computerized cognitive behavioral therapy program to treatment as usual, showing that the therapy significantly improved symptoms of depression, anxiety, and insomnia (Liu et al., 2021). In Chinese hospitalized patients, progressive muscle relaxation improved negative emotions, anxiety, and sleep (Benzakour & Bondolfi, 2022). Posttraumatic stress disorder-specific approaches have not been evaluated in COVID-19, though exposurebased treatments and cognitive therapies have the greatest established efficacy (Brown et al., 2018). A group psychotherapy for those with psychological stress associated with Long COVID identified major themes of envy, disruption of attachments, lack of faith in medicine, information sharing, coping with uncertainty, alienation/invalidation from the medical community, and hope in the face of ongoing physical suffering (Padda et al., 2022).

Somatization, Somatic Symptom Disorder, and Medically Unexplained Symptoms Diagnoses implicating psychological origin of physical symptoms have a complex and controversial history. Historically, both the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders-5 classification systems have required somatoform disorders to be medically unexplained (North, 2015). The most recent revision of the Diagnostic and Statistical Manual of Mental Disorders-5 (American Psychiatric Association, 2022) defines somatic symptom disorder as: One or more somatic symptoms that are distressing or result in significant disruption of daily life AND excessive thoughts, feelings, or behaviors related to the somatic symptoms or associated health concerns as

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manifested by at least one of the following: disproportionate and persistent thoughts about the seriousness of one’s symptoms AND/OR persistently high level of anxiety about health or symptoms AND/OR excessive time and energy devoted to these symptoms or health concerns. An important change from prior editions is that the condition no longer needs to be medically unexplained, and therefore it is no longer a diagnosis of exclusion. This allows for making the diagnosis of somatic symptom disorder in someone who is experiencing symptoms of a known medical condition. Clinicians with outdated diagnostic approaches may continue to treat individuals as though somatic spectrum illnesses are mutually exclusive with a “biological” condition, and this is an important area in which a mental healthcare provider can offer education. However, the Diagnostic and Statistical Manual of Mental Disorders-5 definition is complicated by its designations of excessive, persistently high, and disproportionate. Considering that these labels are all subjective, there exists much room for their erroneous use when a provider is unaware of the heterogeneity in disease presentation and the range in expected severity of a given disease. Long COVID patients are particularly at risk. Clinicians must remain mindful of an evolving evidence base and understanding of the disease and its repercussions, with cognitive flexibility around this being especially important when considering assigning a diagnosis of somatic symptom disorder. What may be considered “excessive” or “disproportionate” to one person may not be to another, and further a symptom or reaction may be considered “excessive” or “disproportionate” at one point in time, but not at another. Finally, clinicians must balance the potential benefit of assigning the diagnosis and treating it with the potential repercussions of putting the label in a patient’s record and therefore making them vulnerable to skepticism, stigma, and medical neglect. Freud’s description of “hysterical conversion” understood somatic symptoms as being the result of unconscious thoughts and wishes that were psychologically incompatible with an individual, such that they are pushed into the unconscious in the form of physical symptoms (North, 2015). Adopting this perspective too simplistically may result in over-emphasizing the role of psychology in recovery, shifting blame onto patients for their continued illness, and may result in medical neglect.

Conclusion Mental health conditions following COVID-19 illness are common and vary in severity. The approach to these conditions should consider differential diagnoses while focusing on subjective psychological disturbance in concert with the entirety of the Long COVID clinical syndrome. Pharmacological treatments and psychotherapeutic interventions can aid in treating comorbid psychiatric conditions and psychological distress, with specific considerations

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varying depending on a patient’s medical status and spectrum of symptomatology. Further research may better delineate between treatment approaches that can be more helpful in Long COVID subpopulations.

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Mental Health Disorders  195 COVID-19 and first manic episodes: A systematic review. Psychiatry Research, 314, 114677. https://doi​.org​/10​.1016​/j​.psychres​.2022​.114677 Schou, T. M., Joca, S., Wegener, G., & Bay-Richter, C. (2021). Psychiatric and neuropsychiatric sequelae of COVID-19: A systematic review. Brain, Behavior, and Immunity, 97, 328–348. https://doi​.org​/10​.1016​/j​.bbi​.2021​.07​.018 Sfera, A., Osorio, C., Rahman, L., Zapata-Martín del Campo, C. M., Maldonado, J. C., Jafri, N., Cummings, M. A., Maurer, S., & Kozlakidis, Z. (2021). PTSD as an endothelial disease: Insights from COVID-19. Frontiers in Cellular Neuroscience, 15. https://www​ .frontiersin​.org​/articles​/10​.3389​/fncel​.2021​.770387 Shalev, A., Liberzon, I., & Marmar, C. (2017). Post-traumatic stress disorder. The New England Journal of Medicine, 376(25), 2459–2469. https://doi​.org​/10​.1056​/NEJMra1612499 Sharpe, M., Clements, A., Hawton, K., Young, A. H., Sargent, P., & Cowen, P. J. (1996). Increased prolactin response to buspirone in chronic fatigue syndrome. Journal of Affective Disorders, 41(1), 71–76. https://doi​.org​/10​.1016​/0165​-0327(96)00075-4 Shem, K., Barncord, S., Flavin, K., & Mohan, M. (2018). Adverse cognitive effect of gabapentin in individuals with spinal cord injury: Preliminary findings. Spinal Cord Series and Cases, 4(1), Article 1. https://doi​.org​/10​.1038​/s41394​-018​-0038-y Smith, C. M., Gilbert, E. B., Riordan, P. A., Helmke, N., von Isenburg, M., Kincaid, B. R., & Shirey, K. G. (2021). COVID-19-associated psychosis: A systematic review of case reports. General Hospital Psychiatry, 73, 84–100. https://doi​.org​/10​.1016​/j​.genhosppsych​ .2021​.10​.003 Stefano, G. B. (2021). Historical insight into infections and disorders associated with neurological and psychiatric sequelae similar to long COVID. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 27, e931447-1–e9314474. https://doi​.org​/10​.12659​/MSM​.931447 Sukhatme, V. P., Reiersen, A. M., Vayttaden, S. J., & Sukhatme, V. V. (2021). Fluvoxamine: A review of its mechanism of action and its role in COVID-19. Frontiers in Pharmacology, 12, 652688. https://doi​.org​/10​.3389​/fphar​.2021​.652688 Taquet, M., Geddes, J. R., Husain, M., Luciano, S., & Harrison, P. J. (2021). 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: A retrospective cohort study using electronic health records. The Lancet Psychiatry, S2215036621000845. https://doi​.org​/10​.1016​/S2215​-0366(21)00084-5 Taquet, M., Sillett, R., Zhu, L., Mendel, J., Camplisson, I., Dercon, Q., & Harrison, P. J. (2022). Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: An analysis of 2-year retrospective cohort studies including 1 284 437 patients. The Lancet Psychiatry. https://doi​.org​/10​.1016​/S2215​-0366(22)00260-7 Taylor, R. R., & Jason, L. A. (1998). Comparing the DIS with the SCID: Chronic fatigue syndrome and psychiatric comorbidity. Psychology & Health, 13(6), 1087–1104. https:// doi​.org​/10​.1080​/08870449808407452 Tu, Y., Zhang, Y., Li, Y., Zhao, Q., Bi, Y., Lu, X., Kong, Y., Wang, L., Lu, Z., & Hu, L. (2021). Post-traumatic stress symptoms in COVID-19 survivors: A self-report and brain imaging follow-up study. Molecular Psychiatry, 26(12), 7475–7480. https://doi​.org​/10​ .1038​/s41380​-021​-01223-w Watson, C. J., Thomas, R. H., Solomon, T., Michael, B. D., Nicholson, T. R., & Pollak, T. A. (2021). COVID-19 and psychosis risk: Real or delusional concern? Neuroscience Letters, 741, 135491. https://doi​.org​/10​.1016​/j​.neulet​.2020​.135491 Welton, R. S., & Crocker, E. M. (2021). Supportive therapy in the medically ill: Using psychiatric skills to enhance primary care. The Primary Care Companion for CNS Disorders, 23(1), 26043. https://doi​.org​/10​.4088​/PCC​.20nr02758

196  Mental Health Disorders World Health Organization. (2022, February). ICD-11 for Mortality and Morbidity Statistics. https://icd​.who​.int​/browse11​/l​-m​/en#​/http​%3a​%2f​%2fid​.who​.int​%2ficd​%2fentity​ %2f767044268 Xiao, C.-X., Lin, Y.-J., Lin, R.-Q., Liu, A.-N., Zhong, G.-Q., & Lan, C.-F. (2020). Effects of progressive muscle relaxation training on negative emotions and sleep quality in COVID-19 patients. Medicine, 99(47), e23185. https://doi​.org​/10​.1097​/MD​ .0000000000023185 Yang, Y., Li, W., Zhang, Q., Zhang, L., Cheung, T., & Xiang, Y.-T. (2020). Mental health services for older adults in China during the COVID-19 outbreak. The Lancet. Psychiatry, 7(4), e19. https://doi​.org​/10​.1016​/S2215​-0366(20)30079-1 Zhang, L., Zhou, L., Bao, L., Liu, J., Zhu, H., Lv, Q., Liu, R., Chen, W., Tong, W., Wei, Q., Xu, Y., Deng, W., Gao, H., Xue, J., Song, Z., Yu, P., Han, Y., Zhang, Y., Sun, X., … Qin, C. (2021). SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduction and Targeted Therapy, 6(1), Article 1. https://doi​.org​/10​.1038​/s41392​-021​-00719-9 Zürcher, S. J., Banzer, C., Adamus, C., Lehmann, A. I., Richter, D., & Kerksieck, P. (2022). Post-viral mental health sequelae in infected persons associated with COVID-19 and previous epidemics and pandemics: Systematic review and meta-analysis of prevalence estimates. Journal of Infection and Public Health, 15(5), 599–608. https://doi​.org​/10.1

12 Alternative Treatment Approaches Tae-Hun Kim, KMD, PhD

Many patients have sought complementary and alternative medicine (CAM) interventions as an alternative strategy for the treatment and management for Long COVID symptoms. In fact, during the acute COVID-19 pandemic, both patients with acute COVID-19 infection and heathy individuals used CAM interventions for treating symptoms related to COVID-19 or preventing acute infection. A systematic review of CAM usage during the COVID19 pandemic assessing observational studies of the general population and COVID-19 patients suggests that CAM interventions were used among 64% of the population, and this result is reported to be similar between the healthy population (65%) and COVID-19 patients (63%) (Kim et al., 2022a). These results might be applicable to the management of Long COVID, but there is a need for guidance on the evidence-based evaluation and treatment of CAM interventions for Long COVID. In this chapter, current evidence on the effectiveness of overall CAM interventions for various Long COVID symptoms are reviewed. Next, a summary of widely used CAM interventions is suggested based on the existing research evidence. Because there are not enough studies on Long COVID available, studies regarding CAM interventions covering post-viral symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are reviewed for each individual intervention. This chapter mainly deals with the most frequent symptoms of Long COVID including chronic fatigue, respiratory complications (dyspnea), cognitive impairment (brain fog), gastrointestinal symptoms, anosmia, and mental health (insomnia and depression). CAM interventions covered here include nutrients (and dietary supplements), herbal medicine, acupuncture and related techniques, mind-body therapies including tai chi, meditation (or breathing), and massage.

Overall Evidence Status of CAM Interventions for Long COVID and Ongoing Studies Searching PubMed in May 2022, there were only 25 publications on CAM interventions for Long COVID symptoms and recovery from COVID-19 infection. The most frequent intervention which was reported in these publications DOI: 10.4324/9781003371090-12

Types of interventions

Review

Types of publications

Fatigue and reduced exercise tolerance

Target symptoms or conditions

Evidence of benefit and harm

Potentially effective Brugliera et al. 2020 Nutritional management Treatment protocol Malnutrition No information Castro-Marrero et al. Coenzyme Q10 and NADH RCT Myalgic encephalomyelitis/chronic fatigue Potentially 2021 co- supplementation syndrome effective Cesarone et al. 2022 Pycnogenol® and Centellicum® Case-control study Lung function, fatigue, muscular pain, Potentially supplementation dyspnea effective Marchenkova et al. Vitamins and minerals Systematic review Hypoxic syndrome, asthenic syndrome, Potentially 2021 syndrome of neuropsychiatric disorder, effective gastrointestinal symptoms Menéndez et al. 2022 Vitamin D Review Cognitive impairment, mental health Potentially (anxiety, depression) effective Naureen et al. 2021 A food supplement containing Observational study Fatigue Potentially hydroxytyrosol, acetyl L-carnitine, effective and vitamins B, C, and D Santos 2022 Zinc supplementation Review Diarrhea and ageusia Potentially effective Skesters et al. 2022 Selenium Observational study Not suggested No clinical information Todorov et al. 2021 Probiotics and postbiotics Review Lung tissue damage and impaired lung Potentially function effective Weill et al. 2020 Omega-3 fatty acid Review Inflammation-related damage Potentially effective

Nutritional supplements Barrea et al. 2022 Vitamin D

Study ID

Table 12.1 Summary of the effectiveness of CAM interventions for Long COVID.

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Acupuncture

Traditional Chinese medicine

Ayurveda

Kakkontokasenkyushin’i (THM) Ayurveda and yoga

Ma et al. 2021

Ma et al. 2020

Rajkumar 2020

Takayama et al. 2021 Yadav et al. 2021

Zhang et al. 2022

Tai chi and qigong

Tai chi and qigong Ma et al. 2020a Baduanjin exercise

Combination of pirfenidone and traditional Chinese medicine Traditional Chinese medicine

Lu et al. 2021

Thumb-tack needles based on “Biaoben acupoint compatibility” Mears 2005 Electroacupuncture Zha et al. 2022 Dry needling Traditional medicine (THM, TCM and Ayurveda) Kim et al. 2021 Traditional herbal medicine

Luo et al. 2022

Acupuncture Huang et al. 2020

Psychological sequelae in COVID-19

Systematic review protocol RCT protocol

Systematic review protocol Systematic review protocol

Case series RCT protocol

Review

Systematic review protocol Review

Post-viral fatigue syndrome Myalgia

Case study Case study

Pulmonary function, QOL

QOL, Long COVID symptoms

COVID-19-related olfactory disorder Pulmonary function, fatigue, anxiety and depression, sleep quality, QOL

Symptoms of depression or anxiety

Psychological and mental health

Post-viral olfactory dysfunction

Pulmonary fibrosis

Pulmonary function, anxiety

COVID-19 treatment related AEs

Systematic review protocol RCT

(Continued)

Not suggested

Not suggested

Potentially effective Potentially effective Effective Not suggested

Not suggested

Not suggested

Not suggested

Potentially effective Partially effective Effective

Not suggested

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Massage

Massage Tague et al. 2021 Commentary

Types of publications

Long-term symptoms

Target symptoms or conditions

Research is necessary

Evidence of benefit and harm

Publications on important complementary and alternative (CAM) interventions for Long COVID or recovery from acute COVID-19 infections were located through electronic searching on PubMed in May 2022. AEs: adverse events; NADH: nicotinamide adenine dinucleotide; PVOD: postural olfactory disorder; QOL: quality of life; RCT: randomized controlled trial; TCM: traditional Chinese medicine; THM: traditional herbal medicine.

Types of interventions

Study ID

Table 12.1 Continued

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was nutritional supplements (n=11), followed by traditional medicine (n = 7), acupuncture (n = 4), tai chi (n = 2), and massage (n = 1). Unfortunately, most clinical evidence is only supported by case studies or narrative reviews. Based on Table 12.1, there are few studies involving randomized controlled trials and systematic reviews. Regarding dietary supplements, there are reviews or research evidence of various nutritional interventions including vitamins (e.g., vitamin D), trace elements (e.g., zinc and selenium), probiotics, omega-3 fatty acid, coenzyme Q10, and other supplementary products for Long COVID symptoms. For herbal medicine and acupuncture, a few case studies are available. Traditional Chinese medicine, Ayurveda, tai chi, and massage do not have clinical studies, and only expert opinions and study protocols are available. Brief searching for ongoing studies in the WHO International Clinical Trials Registry Platform in June 2022 yields current clinical trials on dietary supplements (oil products, coenzyme Q10, omega-3 fatty acid, vitamins, etc.), acupuncture (acupressure), traditional medicine (traditional herbal medicines, traditional Chinese medicine, Ayurveda, and yoga), mind-body interventions, and tai chi. Figure 12.1 presents the gap between the publications and registered trials which reflects the status of clinical evidence for each CAM intervention. Only a few publications about various CAM interventions with high certainty of effectiveness for Long COVID symptoms are available (Figure 12.1). Figure 12.1 includes the number of published studies and registered ongoing studies. The bright gray bar represents the number of already published studies which were located through electronic searching on PubMed in May 2022. The dark gray bar represents the number of ongoing studies located through brief searching for trial registry information on the WHO International Clinical Trials Registry Platform in June 2022. Because there is a lack of evidence for treating Long COVID with these alternative approaches, below we summarize the potential effect of these interventions for frequent conditions of Long COVID based on the available research evidence.

Figure 12.1  Research status of complementary and alternative medicine (CAM) interventions for Long COVID.

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Dietary Supplements, Medicinal Herbs, and Traditional Medicine Various dietary supplements have been studied and used for presumptive immune-boosting or anti-viral effects. During the asymptomatic phase of acute COVID-19 infection, vitamin D, curcumin, probiotics, propolis, and selenium have been suggested to promote anti-viral effects through host-immune boosting (Mrityunjaya et al., 2020). In addition, vitamin D, vitamin C, selenium, curcumin, cinnamaldehyde, and piperine are expected to have effects on modulating over-active inflammatory reactions and cytokine storm during the symptomatic phase (Mrityunjaya et al., 2020). It has been reported that probiotics might have the potential to improve respiratory tract symptoms which are introduced by direct damage from SARS-CoV-2 or indirect damage from a hyperactive immune response to the virus (Todorov et al., 2021). During the pandemic, the consumption and sales of certain supplementary products (such as zinc, vitamin C, and vitamin D) showed considerable increases (Grebow, 2020). However, the research evidence for whether these dietary supplements are effective in COVID-19 infection is still unclear. For example, vitamin D is generally accepted to be an active immune booster from influenza virus through maintaining cell barrier integrity and promoting immunity against viral infection. Vitamin D is critical in the bone metabolism and involved in human immunity and energy metabolism (Tosato et al., 2022). Martineau et al. (2017) found that vitamin D supplementation is helpful in reducing acute respiratory tract infections. It has been reported that deficiency of vitamin D is related to decreased memory and cognitive function in animal studies, which suggests a potential effect of vitamin D for brain fog in post-COVID 19 patients (Ali et al., 2021). However, only a weak negative trend could be observed between the serum level of vitamin D and the risk of severe clinical results in COVID-19 patients. In addition, different studies on the effectiveness of vitamin D supplementation suggested conflicting results with respect to the direction of the effect (Bassatne et al., 2021). 25-hydroxyvitamin D, a form of vitamin D, is the indicator for assessing vitamin D level in the body. Townsend et al. (2021) assessed the level of total 25-hydroxyvitamin D concentration in patients with COVID-19 with persistent symptoms in the recovery phase and found that a low concentration of vitamin D did not show any meaningful relationship with fatigue level and physical performance (Townsend et al., 2021). In addition, vitamin D is expected to be effective in inhibiting a cytokine storm which introduces a hyperinflammatory reaction in the respiratory tract and in the injured lung tissue during the acute infection stage. However, there is not sufficient evidence on the effectiveness of vitamin D for the recovery of pulmonary complications of COVID-19, either (Barrea et al., 2022). Zinc, selenium, and iron are essential trace elements for maintaining normal functioning of the body, and deficiency of these elements is frequently

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observed among patients in the severe course of diseases. Therefore, it is possible that supplementation with these trace elements could be beneficial for patients with Long COVID. Zinc is an important element for human immunity and cell homeostasis, and its deficiency is closely related to acute and longlasting symptoms of respiratory tract infection (Skalny et al., 2020; Tosato et al., 2022). Anosmia (alone or with dysgeusia), one of the common symptoms of Long COVID, is presumed to be related to zinc deficiency (Propper, 2021). In addition to this, damage to the gastrointestinal epithelium by SARS-CoV-2, cytokine storm, or prolonged antibiotic usage may be the potential pathology of COVID-19-related diarrhea; zinc supplementation can mitigate this symptom, which should be supported by future clinical studies (Santos, 2022). Selenium is also an important trace element which is involved in the physiological function of the body. It has been reported that selenium deficiency might be related to a severe clinical presentation in patients with COVID-19, and its potential mechanism is explained by increased oxidative stress (Skesters et al., 2022). In addition to this, prolonged recovery from COVID-19 infection might be related to a selenium deficiency (Schomburg, 2021; Tosato et al., 2022). Iron is a necessary element which is used for oxygen transport, and a low serum level of iron has been reported to be associated with respiratory insufficiency and mortality in acute COVID-19 infection (Zhao et al., 2020). Iron supplementation may be considered for vulnerable patients for reducing Long COVID symptoms and improving immune response related to vaccination (Tosato et al., 2022). Diarrhea, loss of appetite, and nausea (and vomiting) are common gastrointestinal symptoms which are partially related to the gut dysbiosis (i.e., the loss of beneficial microbial input or expansion of pathogenic microbes) from long-term antibiotic usage and stress (Liu et al., 2022). Probiotics, which are living microbial dietary supplements, have been found to have health benefits for several indications such as antibiotic-associated diarrhea, infectious diarrhea, and lactose intolerance through improving the balance of intestinal flora (Kechagia et al., 2013). It is certainly possible that probiotics supplementations may be helpful for patients with gastrointestinal symptoms after COVID infection (Tosato et al., 2022). Omega-3 fatty acid may be beneficial in reducing severe complications caused by the inflammation-related damage in patients with COVID-19. Severe COVID-19 cases have been reported to have low serum omega-3 fatty acid levels (Zapata et al., 2021). Omega-3 fatty acid, which has antiviral effects on the entry and replication of SARS-CoV-2, may be effective in resolving inflammatory imbalance (Weill et al., 2020). For Long COVID patients, omega-3 fatty acid may have beneficial effects in mood disorders and cognitive dysfunction as well as cleansing remaining inflammation and restoring damaged tissue (Yang et al., 2022a). Coenzyme Q10 (ubiquinone) is a key component in the mitochondria respiratory chain and can be a potent antioxidant (Sifuentes-Franco et al., 2022).

204  Alternative Treatment Approaches

Coenzyme Q10 has been reported to be helpful for patients with chronic fatigue (Ernster and Dallner, 1995). Twelve weeks of coenzyme Q10 and nicotinamide adenine dinucleotide supplementation showed significant improvement in cognitive function and fatigue perception as well as quality of life when compared with placebo control in individuals with ME/CFS (Castro-Marrero et al., 2021). Mitochondrial dysfunction may be reduced by coenzyme Q10 supplementation, which then may help in the treatment of fatigue symptoms in patients with Long COVID. Currently, evidence on the effect of most dietary supplements summarized above is not supported by randomized studies; possible treatments can be recommended based on potential biological mechanism. In this sense, future randomized controlled trials and systematic reviews are necessary for establishing evidence of each dietary supplement for Long COVID. Various herbal foods or products such as tea, ginger, black seed, honey, clove, cinnamon, garlic, etc., have been widely used as preventative measures during the COVID-19 pandemic, because medicinal herbs are comparatively easy to access everywhere (Ahmed et al., 2020). There are several medicinal herbs which can be applied for Long COVID symptoms. For example, ginseng is one of the most frequently used herbal supplements for both healthy people and patients with various conditions including erectile dysfunction, cognitive disorders, diabetes, and cardiovascular disease (Lee and Son, 2011). Ginseng has been found to be a safe and effective intervention for fatigue patients with both chronic illness and ME/CFS (Arring et al., 2018; Yang et al., 2022b). Withania somnifera is one of the popular medicinal herbs in Ayurvedic medicine, and there is evidence for clinical effectiveness for those with mild cognitive impairments and psychological disorders (Ng et al., 2020). More research will be needed for medicinal herbs and their possible benefits for patients with Long COVID. During the COVID-19 pandemic, treatment guidelines (or protocols) have been published for traditional Chinese medicine, Korean medicine, and Ayurveda (Lee et al., 2020; Ning et al., 2020; Pandit et al., 2020) which include recommendations of potential herbal medications and other non-drug traditional interventions for COVID-19 patients. Rajkumar (2020) summarized the Indian government’s Ayurvedic practice guideline for COVID-19 and noted indications of Ayurvedic interventions and their potential mechanism: the use of spices such as turmeric, coriander, cumin, garlic, and golden milk (warm milk with turmeric) may be effective in the modulation of the expression of monoamine and gamma-amino butyric acid which results in the improvement of depression. Taking Chyawanrash (traditional herbal medicine) and drinking herbal tea (basil, cinnamon, black pepper, ginger, and raisins) may be helpful for depression, anxiety, and stress (Rajkumar, 2020). Likewise, various types of herbal medications are also expected to have potential for Long COVID symptoms. Kakkontokasenkyusin’i is a frequently used herbal extract in Japan, China, and Korea for upper respiratory tract infection and rhinitis. Takayama et al.

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(2021) published a case series study of five patients with COVID-19-related olfactory disorder. Patients had symptoms including nasal discharge (or blockage), anosmia, and taste impairment after COVID-19 infection. With only 3 to 5 days of administration for this herbal medication, patients reported that the function of smell and taste was significantly restored (Takayama et al., 2021). Ma et al. reviewed the literature on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) to propose potential treatments for mental illness in COVID-19 survivors. They suggested that traditional herbal medications including Ganmai Dazao decoction, Lily Bulb and Anemarrhena decoction, Suanzaoren decoction, Huanglian Ejiao decoction, etc., may be helpful for mental disorders such as depression, anxiety, and posttraumatic stress disorder (Ma et al., 2020b). Currently, traditional Chinese medicine and Ayurveda are among the most active clinical research areas for Long COVID and post-COVID-19 recovery in the CAM field. For post-COVID recovery, Qing-Jin Yi-Qi granule, Shuiman capsule, Sheng-Mai-Yin, Gu-Shen Ding-Chuan-Wan, and other individualized herbal decoctions are being evaluated in China. Xiaoyao capsule, Shugna Jieyu capsule, and other traditional Chinese medicine psychological interventions are being evaluated for sleep and mood disorders. These study results will determine the clinical evidence for the traditional medicine interventions for Long COVID.

Acupuncture and Related Techniques Acupuncture is an intervention or technique whose principle and practice originated in traditional East Asian medicine. Acupuncture needles, which are usually disposable stainless-steel needles, are inserted into specific points of the body (acupoints) and are manually or electrically stimulated for treating various conditions. Sometimes instead of needling, heat stimulation (moxibustion, burning dried mugwort), acupoint massage (acupressure), or other medical devices (magnet, catgut, etc.) can be applied (Acupuncture Therapy, 2022). Acupuncture is considered to be a safe and effective intervention for chronic fatigue and cognitive dysfunction which are common conditions in patients with Long COVID (Li et al., 2020). Zhang et al. (2019) conducted a systematic review on the effects of acupuncture for ME/CFS. Sixteen studies (1,346 patients) were included in the analysis, and acupuncture showed favorable results in overall clinical response rate. Mental and physical fatigue showed significant improvements for those provided acupuncture. Only one study suggested mild adverse events including redness, itching, and regional pain. There is considerable clinical heterogeneity in the selection of acupoints and treatment duration. BL18, BL20, BL 23, ST36, and GV20 were the mostly frequently mentioned. In addition, acupuncture was treated for 4 weeks in most studies (ranging from 2 weeks up to 4 months) (Zhang et al., 2019). One published systematic review suggested potential positive effects of acupuncture for mild cognitive impairment (Li et al., 2020). This review included 15

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randomized controlled trials evaluating the effects of acupuncture for mild cognitive impairment in the elderly population. Most studies did not report any adverse events, suggesting the safety of acupuncture. Acupuncture was treated for 1 to 3 months, which showed considerable heterogeneity in the included studies. The authors found that the acupuncture group showed improvement in mini-mental state examination scores, activity of daily living scale, and clinical efficacy rate (Li et al., 2020). There is one study that has examined the effectiveness of acupuncture for postinfectious anosmia or smell loss. Drews et al. (2022) conducted a controlled study evaluating the effects of 12 acupuncture (or sham acupuncture) treatments on the face, hand, and foot acupoints. Patients were recruited who had anosmia following an upper respiratory tract infection without any neurological pathologies or chronic infection in the nasal cavity. After treatment, acupuncture group showed significant improvement in the olfactory threshold, discrimination, and identification scores but no improvement in the sham acupuncture group. In addition, acupuncture showed significant improvement in odor discrimination function and shorter anosmia symptom duration (Drews et al., 2022). In addition, there is a case report on the effects of acupuncture for post-viral olfactory dysfunction. A 55-year-old woman who had post-viral anosmia was treated with 3 months of manual acupuncture (Yintang, BL2, LI20, CV24, GV20, GV22, GV24, and GV26). After treatment, there was a 95% improvement in her normal ability to smell and taste without any adverse events (Hunter et al., 2021). Currently randomized controlled trials which assess the effect of manual (or auricular) acupuncture for olfactory dysfunction after COVID-19 infection or Long COVID patients are being conducted, and these study results will suggest clinical evidence of acupuncture for COVID19-related anosmia. Based on the review of existing studies above, acupuncture may be helpful for some of the symptoms of Long COVID, including chronic fatigue, cognitive impairments, and anosmia. In one of the few studies with COVID patients, Luo et al. (2022) conducted a randomized controlled trial evaluating the effect of acupuncture for patients in the recovery phase of COVID-19 infection. Patients were randomly assigned to an acupuncture group (14 sessions of thumb-tack needle acupuncture at CV4, ST36, and LU9) or an observational group. After treatment, anxiety scores, depression scores, and pulmonary function showed significant improvement in the acupuncture group (Luo et al., 2022). There are also several case studies which showed clinical improvements for patients with Long COVID after acupuncture treatment. For example, Hollifield et al. (2022) described a patient who was treated with acupuncture. This patient had various Long COVID symptoms including pulmonary symptoms (chest pain, shortness of breath), fatigue and brain fog, eye dryness, and pain (knee and finger). Twelve acupuncture treatments on SP10, LU7, KD6, LI4, LR3, ST36, SP6, LR8, TH5, GB42, HT7, SP9, and Yintang showed considerable improvement in pulmonary symptoms and brain fog. However, there was no improvement in pain and fatigue. Another case report suggested

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clinical improvement of post-COVID19 syndrome through a multidisciplinary approach. A 50-year-old patient who had 8 months of fatigue, anosmia, and pulmonary symptoms after COVID-19 infection was successfully treated with 7 sessions of acupuncture treatments (ST36, LI4, LU7, TE5, and GB3) and physical therapy (symptom-titrated physical activity program). The patient who participated in the treatment was able to return to normal daily life after treatment and felt physically improved (Trager et al., 2022). Based on the limited data available, the evidence on the effectiveness of acupuncture for Long COVID is still unclear. Several acupuncture interventions and related interventions (electrical stimulation and acupressure) are currently being planned or tested for COVID-related fatigue, so hopefully these studies will provide the evidence that is needed in this area.

Mind-Body Therapies (Tai Chi, Yoga, Meditation, and Breathing Exercise) Meditation, relaxation techniques, massage, tai chi, yoga, and even acupuncture are included in the mind-body therapies (Mind body practices, 2022). Meditation has been used for relieving anxiety and depression, and it has been helpful in patients with insomnia, irritable bowel syndrome, and ulcerative colitis (Meditation, 2022). Yoga, which is one of the traditional practices of Ayurvedic medicine, includes exercise with breathing controls (Yoga, 2022). Tai chi originated from the Chinese martial arts but has been modified into a gentler exercise which might be beneficial to elders or patients with chronic diseases through improving balancing and physiological function. Tai chi has been used effectively with patients with knee osteoarthritis and chronic diseases such as Parkinson’s disease, cancer, and heart diseases (Mind body practices, 2022). A recent systematic review suggested that mind-body interventions are shown to be effective in relieving fatigue, anxiety, depression, and physical function, although there are methodological limitations in the studies (Khanpour Ardestani et al., 2021). Systematic review suggests that cancer, musculoskeletal diseases, and affective mood disorders were the most frequently tested conditions for meditation (Kim et al., 2022b). Meditation has been effective with insomnia and fatigue, and it might therefore be effective for similar symptoms in patients with Long COVID (Kim et al., 2022b). Porter et al. (2010) conducted a review on the effect of mind-body therapies for ME/CFS and fibromyalgia and meditation was one of the most effective interventions for this condition. In one study, daily meditation using a mobile app for 8 weeks led to improved fatigue and sleep problems for patients with sleep disturbance (Huberty et al., 2021). In addition to fatigue and insomnia, meditation-based interventions may be effective in improving cognitive function and daily activities in patients with dementia. Hoffman et al.’s (2020) review of 19 studies of patients with dementia concluded that improvement of cognitive function after meditation was observed (Hoffman et al., 2020). The mechanism of meditation for the improvement

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in these conditions is considered to be related to the functional and structural regulation in multiple brain regions (Tang et al., 2015). Tai chi (qigong) is a commonly used intervention for improving the health status of various diseases. Tai chi consists of slow movement with meditation and breathing which can be effective in balancing, aerobic capacity, immune function, and psychological well-being (Xiang et al., 2017). A systematic review suggested that tai chi was effective in treating fatigue compared to conventional medicine therapies or low-impact exercise controls (Xiang et al., 2017). From this systematic review, 50 minutes of tai chi training seems to be more helpful for fatigue regardless of the whole length and frequency of the training. In addition, another systematic review suggests that Baduanjin (one type of qigong exercise) can be effective in enhancing cognitive function and memory for senior citizens without any adverse effects (Wang et al., 2021a). Ongoing clinical trials on tai chi (qigong exercise) are currently focusing on whether improvement in the pulmonary function and quality of life can occur in patients who are in the recovery phase of severe COVID-19 infection. Yoga includes physical exercise, breathing, and meditation for mental control and well-being (Yoga, 2022). Yoga may have beneficial effects for patients with COVID-19 because it is helpful to normalize excessive immune response by decreasing pro-inflammatory biomarkers and increasing anti-inflammatory biomarkers (Shah et al., 2022). Yoga training is effective with stress, depression, and anxiety (Basu-Ray et al., 2022). A systematic review on the effectiveness of yoga for fatigue suggested that 5 to 24 weeks of yoga training showed favorable effects on fatigue in patients with various conditions (cancer, multiple sclerosis, chronic pancreatitis, fibromyalgia, asthma) (Boehm et al., 2012). Current evidence also suggests beneficial effects of yoga for cognitive dysfunction. Brenes et al. (2019) found that 8 to 18 weeks of yoga training in patients with mild cognitive impairments or Alzheimer’s dementia showed meaningful improvements in cognitive functioning (attention and verbal memory), and sleep and mood (depression and resilience) (Brenes et al., 2019). Breathing exercise (or respiratory muscle training) can be defined as a specific exercise program which includes deepening of inspiration and expiration or changing the rhythm of respiration (Borge et al., 2014). Breath control exercises cover a wide variety of interventions such as diaphragm breathing, yoga breathing, relaxing exercise, and pursed-lip breathing (Borge et al., 2014). A systematic review on the effects of breathing exercise for chronic obstructive pulmonary disease can offer insight for the usage of these techniques for patients with Long COVID. Patients with chronic obstructive pulmonary disease have breathlessness and symptoms which are related to shallow breathing and increased respiratory rate due to the chronic obstruction of airways. Evidence suggests that breathing exercises for this population can improve breathlessness and patients’ quality of life (Borge et al., 2014). From this point of view, breathing exercises may be helpful to patients with pulmonary complications after acute COVID-19 infection.

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The practitioners and patients of mind-body therapy interventions do not always need to have face-to-face meetings for the treatments. Therefore, if a web-based platform is available, restrictions on access to treatments might be reduced. This is one of the advantages of mind-body therapies. This feature is beneficial in situations where direct person-to-person contact is difficult, such as during the COVID-19 pandemic.

Massage Massage therapy may be a useful treatment strategy for symptom management for patients with Long COVID. Massage consists of gentle stimulation of the skin, muscles, and soft tissues of the body. It aims to improve lymphatic circulation and to affect relaxation of muscles (Massage 2022). Massage is effective for mood disturbance and physical discomfort in cancer patients (Listing et al., 2009). Massage has also showed effectiveness for fatigue in breast cancer survivors (Wang et al., 2021b). During the pandemic, massage was suspended in many places due to its nature of personal contact. However, hospital-based massage therapy continued to be used for reducing anxiety, improving immune function, and symptom management in cancer patients (Tague et al., 2021). One thing which should be considered about the evidence for massage therapy is that the frequency and duration of massage may be related to the biological effects (Rapaport et al., 2012). Previous research suggests that only 20 minutes of massage during chemotherapy demonstrated good satisfaction and significant improvement of pain, fatigue, and anxiety (Robison and Smith, 2016). Clinical studies are needed to determine the optimal method and frequency of massage for symptom management of Long COVID.

Conclusion CAM interventions such as dietary supplements, mind-body therapies, acupuncture, and traditional medicine might have potential benefits for Long COVID patients. In general, most CAM interventions are accepted to be safe, and serious adverse events are expected to be rare. CAM interventions can be suggested to patients with Long COVID symptoms unless severe safety issues are involved. Currently, however, there is insufficient evidence for the effectiveness of these interventions. We will in the future know more about the evidence for CAM interventions for Long COVID symptoms as there are many ongoing clinical trials. Because of the diverse nature of Long COVID and CAM interventions, more clinical research needs to be promoted in future.

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Alternative Treatment Approaches  213 Ning, L., Yanfang, M., Jingya, W., Huizhen, L., Xiaohui, W., Liwen, J., . . . & Xufei, L. (2020). Traditional Chinese medicine guidelines for coronavirus disease 2019. Journal of Traditional Chinese Medicine, 40(6), 891. Pandit, R. D., & Singh, R. K. (2020). COVID-19 Ayurveda treatment protocol of governments of Nepal and India: A review and perspective. Applied Science and Technology Annals, 1(1), 72–80. Porter, N. S., Jason, L. A., Boulton, A., Bothne, N., & Coleman, B. (2010). Alternative medical interventions used in the treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia. The Journal of Alternative and Complementary Medicine, 16(3), 235–249. Propper, R. E. (2021). Smell/taste alteration in COVID-19 may reflect zinc deficiency. Journal of Clinical Biochemistry and Nutrition, 68(1), 3–3. Rajkumar, R. P. (2020). Ayurveda and COVID-19: Where psychoneuroimmunology and the meaning response meet. Brain, Behavior, and Immunity, 87, 8–9. Rapaport, M. H., Schettler, P., & Bresee, C. (2012). A preliminary study of the effects of repeated massage on hypothalamic–pituitary–adrenal and immune function in healthy individuals: A study of mechanisms of action and dosage. The Journal of Alternative and Complementary Medicine, 18(8), 789–797. Robison, J. G., & Smith, C. L. (2016). Therapeutic massage during chemotherapy and/ or biotherapy infusions: Patient perceptions of pain, fatigue, nausea, anxiety, and satisfaction. Clinical Journal of Oncology Nursing, 20(2). Santos, H. O. (2022). Therapeutic supplementation with zinc in the management of COVID-19–related diarrhea and ageusia/dysgeusia: Mechanisms and clues for a personalized dosage regimen. Nutrition Reviews, 80(5), 1086–1093. Schomburg, L. (2021). Selenium deficiency due to diet, pregnancy, severe illness, or COVID-19: A preventable trigger for autoimmune disease. International Journal of Molecular Sciences, 22(16), 8532. Shah, K., Adhikari, C., Saha, S., & Saxena, D. (2022). Yoga, immunity and COVID-19: A scoping review. Journal of Family Medicine and Primary Care, 11(5), 1683–1701. Sifuentes-Franco, S., Sánchez-Macías, D. C., Carrillo-Ibarra, S., Rivera-Valdés, J. J., Zuñiga, L. Y., & Sánchez-López, V. A. (2022). Antioxidant and anti-inflammatory effects of coenzyme Q10 supplementation on infectious diseases. Healthcare, 10(3), 487. Skalny, A. V., Rink, L., Ajsuvakova, O. P., Aschner, M., Gritsenko, V. A., Alekseenko, S. I., . . . & Aaseth, J. (2020). Zinc and respiratory tract infections: Perspectives for COVID19. International Journal of Molecular Medicine, 46(1), 17–26. Skesters, A., Kustovs, D., Lece, A., Moreino, E., Petrosina, E., & Rainsford, K. (2022). Selenium, selenoprotein P, and oxidative stress levels in SARS-CoV-2 patients during illness and recovery. Inflammopharmacology, 30(2), 499–503. Tague, C., Seppelfrick, D., & MacKenzie, A. (2021). Massage Therapy in the Time of COVID-19. The Journal of Alternative and Complementary Medicine, 27(6), 467–472. Takayama, S., Arita, R., Ono, R., Saito, N., Suzuki, S., Kikuchi, A., . . . & Ishii, T. (2021). Treatment of COVID-19-related olfactory disorder promoted by kakkontokasenkyushin'i: A case series. The Tohoku Journal of Experimental Medicine, 254(2), 71–80. doi:10.1620/tjem.254.71 Tang, Y.-Y., Hölzel, B. K., & Posner, M. I. (2015). The neuroscience of mindfulness meditation. Nature Reviews Neuroscience, 16(4), 213–225. Todorov, S. D., Tagg, J. R., & Ivanova, I. V. (2021). Could probiotics and postbiotics function as "Silver Bullet" in the post-COVID-19 era? Probiotics and Antimicrobial Proteins, 13(6), 1499–1507. doi:10.1007/s12602-021-09833-0

214  Alternative Treatment Approaches Tosato, M., Ciciarello, F., Zazzara, M. B., Pais, C., Savera, G., Picca, A., . . . & Marzetti, E. (2022). Nutraceuticals and dietary supplements for older adults with long COVID. Clinics in Geriatric Medicine, 565–591. Townsend, L., Dyer, A. H., McCluskey, P., O’Brien, K., Dowds, J., Laird, E., . . . & Byrne, D. G. (2021). Investigating the relationship between vitamin D and persistent symptoms following SARS-CoV-2 infection. Nutrients, 13(7), 2430. Trager, R. J., Brewka, E. C., Kaiser, C. M., Patterson, A. J., & Dusek, J. A. (2022). Acupuncture in multidisciplinary treatment of post-COVID-19 syndrome: A case report. Medical Acupuncture, 34(3), 177–183. Wang, X., Wu, J., Ye, M., Wang, L., & Zheng, G. (2021). Effect of Baduanjin exercise on the cognitive function of middle-aged and older adults: A systematic review and metaanalysis. Complementary Therapies in Medicine, 59, 102727. Wang, T., Zhai, J., Liu, X.-L., Yao, L.-Q., & Tan, J.-Y. B. (2021). Massage therapy for fatigue management in breast cancer survivors: A systematic review and descriptive analysis of randomized controlled trials. Evidence-Based Complementary and Alternative Medicine, 2021, 1–13. Weill, P., Plissonneau, C., Legrand, P., Rioux, V., & Thibault, R. (2020). May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients? Biochimie, 179, 275–280. doi:10.1016/j.biochi.2020.09.003 Xiang, Y., Lu, L., Chen, X., & Wen, Z. (2017). Does Tai Chi relieve fatigue? A systematic review and meta-analysis of randomized controlled trials. Plos One, 12(4), e0174872. Yadav, B., Rai, A., Mundada, P. S., Singhal, R., Rao, B. C. S., Rana, R., & Srikanth, N. (2021). Safety and efficacy of Ayurvedic interventions and Yoga on long term effects of COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials, 22(1), 378. doi:10.1186/s13063-021-05326-1 Yang, C.-P., Chang, C.-M., Yang, C.-C., Pariante, C. M., & Su, K.-P. (2022). Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19. Brain, Behavior, and Immunity, 103, 19–27. Yang, J., Shin, K.-M., Abu Dabrh, A. M., Bierle, D. M., Zhou, X., Bauer, B. A., & Mohabbat, A. B. (2022). Ginseng for the treatment of chronic fatigue syndrome: A systematic review of clinical studies. Global Advances in Health and Medicine, 11, 2164957X221079790. Yoga. https://www​.ncbi​.nlm​.nih​.gov​/mesh​/68015013, lastly assessed in August, 2022. Zapata B. R., Müller, J. M., Vásquez, J. E., Ravera, F., Lago, G., Cañón, E., . . . & Ramírez-Santana, M. (2021). Omega-3 index and clinical outcomes of severe COVID19: Preliminary results of a cross-sectional study. International Journal of Environmental Research and Public Health, 18(15), 7722. Zha, M., Chaffee, K., & Alsarraj, J. (2022). Trigger point injections and dry needling can be effective in treating long COVID syndrome-related myalgia: A case report. Journal of Medical Case Reports, 16(1), 31. doi:10.1186/s13256-021-03239-w Zhang, Q., Gong, J., Dong, H., Xu, S., Wang, W., & Huang, G. (2019). Acupuncture for chronic fatigue syndrome: A systematic review and meta-analysis. Acupuncture in Medicine, 37(4), 211–222. Zhang, Z., Ren, J. G., Guo, J. L., An, L., Li, S., Zhang, Z. C., . . . & Lei, X. (2022). Effects of tai chi and qigong on rehabilitation after COVID-19: A protocol for systematic review and meta-analysis. BMJ Open, 12(3), e059067. doi:10.1136/bmjopen-2021-059067 Zhao, K., Huang, J., Dai, D., Feng, Y., Liu, L., & Nie, S. (2020). Serum iron level as a potential predictor of coronavirus disease 2019 severity and mortality: A retrospective study. In Open Forum Infectious Diseases, 7(7). US: Oxford University Press.

13 Menstrual Cycle and Female Reproductive Health Disturbance in the Covid Era Michelle Maher, MD, Laura O’Doherty, MD, and Lisa Owens, MD PhD

COVID-19 is a novel, infectious, multi-system disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Zhou et al., 2020). Despite similar numbers of men and women testing positive for COVID-19 infection, more men have died from this infection than women (N. T. Nguyen et al., 2021), which has led to hypotheses that female sex hormones may be in some way protective against severe COVID-19 infection. Since the beginning of the pandemic, however, there have been reports of menstrual changes related to COVID-19 infection, as well as COVID-19 vaccination (Baena-García et al., 2022; Edelman et al., 2022). There have been studies linking menstrual cycle disturbance to the impact of the pandemic and associated mitigation measures and psychological disturbance (Maher et al., 2022; Phelan et al., 2021). Smallscale studies have also found menstrual cycle disturbance in women with Long COVID (Davis et al., 2021; Newson et al., 2021). In fact, Long COVID is more prevalent in women of reproductive age (Sigfrid et al., 2021). However menstrual irregularities are common, as is being infected with or vaccinated against COVID-19 (Kwak et al., 2019; Maity et al., 2022). Additionally, there is likely to be significant bias in existing studies in this field. There are many varied causes for menstrual disturbances including mental health conditions, medical illness (e.g. polycystic ovary syndrome, endometriosis), medications, and changes in weight (Adcock et al., 1994; Ansong et al., 2019; Bae et al., 2018; Uguz et al., 2012). Socioeconomic circumstances may also increase or decrease a woman’s risk of smoking, developing diabetes, and obesity and so also put her at higher risk of menstrual disturbances (Kwak et al., 2019). More than 78% of the healthcare workers in Europe are female, meaning women have borne the brunt of healthcare facility occupational exposure to this illness (Eurostat, 2019). Women have also been disproportionately impacted by school and childcare closures. In general, women experience inequality in the workplace and the home (Cerrato & Cifre, 2018). This inequality has been deepened by the pandemic and the ensuing mitigation measures (UNFPA, 2020). Working mothers experienced increasing housework and caregiving burdens and were more likely to leave the workforce (Thomas et al., 2021). Pandemic mitigation measures led to loss of services available to vulnerable DOI: 10.4324/9781003371090-13

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children (Our World in Data, 2020). Learning loss was found to be most pronounced in students from disadvantaged homes (Engzell et al., 2021). It has been shown that childhood adversity may have an effect on reproductive/ menstrual health later in life (Jacobs et al., 2015). In this chapter we will discuss what is known about the short- and longterm impact of COVID-19 infection, the COVID-19 pandemic and associated mitigation measures, COVID-19 vaccination, and Long COVID on female reproductive health. In general, studying menstrual cycle changes is challenging, due to the subjectivity of symptoms as well as normal variation over the lifespan. In addition, COVID-19 studies and vaccine trials have not included questions about menstrual cycles. As is often the case, menstruation is a low priority in medical research, and this is no different in relation to COVID19 research. Therefore, it is not clear how prevalent menstrual cycle changes are, how long these changes persist, or whether reported menstrual changes reflect normal fluctuations in menstrual symptoms over time. While there are considerable research gaps, and little in the way of long-term data or clinical practice guidance, we will also discuss what we, the authors, consider a pragmatic clinical approach to menstrual cycle or reproductive health issues arising in this setting.

The Impact of SARS-CoV-2 Infection on Reproductive Health In this section, we will explore potential mechanisms by which SARS-CoV-2 infection may affect female reproductive health, and whether this has translated to significant menstrual disturbance in the setting of acute COVID-19 illness. There are several plausible mechanisms by which SARS-CoV-2 infection may impact on the hypot​halam​ic-pi​tuita​ry-ov​arian​-endo​metri​al axis to alter the menstrual cycle (Davies & Kadir, 2012; Malik et al., 2006; Maybin & Critchley, 2015; Maybin et al., 2018; Sharp et al., 2021). The ACE2 receptor, through which SARS-CoV-2 gains cellular access, is widely expressed in tissues, including the ovaries and endometrium (Chadchan et al., 2021). As a result, SARS-CoV-2 infection may hypothetically affect the endometrial response at menses and/or ovarian hormone production (Sharp et al., 2021). Indeed, it has been shown that knockdown of ACE2 impairs the human endometrial stromal cell decidualization process (Chadchan et al., 2021). This suggests that SARS-CoV-2 may be able to enter endometrial stromal cells and bear negative implications for women with COVID-19, particularly in pregnancy. Furthermore, the local presence of SARS-CoV-2 in the reproductive tract could induce a cascade of immune disruption. For example, acute infection may change the volume and phenotype of endometrial leucocytes which could alter menstrual blood loss (Maybin & Critchley, 2015; Sharp et al., 2021). COVID-19 infection may also impact the female reproductive tract through endothelial cell dysfunction, a known contributor to the initiation and propagation of severe COVID-19 in particular (Teuwen et al., 2020). Abnormalities of factors essential for endothelial cell behavior are seen in women with heavy

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menstrual bleeding (Malik et al., 2006). Endothelial cell dysfunction secondary to SARS-CoV-2 infection may lead to impaired vasoconstriction of endometrial spiral arterioles resulting in increased menstrual blood loss (Sharp et al., 2021). Similarly, COVID-19 causes dysregulation of the coagulation system, another key component of endometrial function at menstruation (Fatimazahra et al., 2021; Teuwen et al., 2020). The cessation of menstruation relies on an intact endometrial coagulation system to achieve hemostasis through platelet aggregation, fibrin deposition, and thrombus formation (Davies & Kadir, 2012). Therefore, alterations in menstrual blood loss may occur where SARSCoV-2 infection interferes with systemic hemostasis (Maybin & Critchley, 2015). In parallel, there have been a small number of case reports of women presenting with ovarian vein thrombosis in the setting of COVID-19 infection (Fatimazahra et al., 2021). Finally, critical illness from COVID-19 may induce hypothalamic amenorrhea, a protective mechanism which occurs in the setting of severe illness to divert energy resources from reproduction to the immune response (McDade, 2005). A limited number of studies have evaluated the impact of acute COVID19 infection on female reproductive health (Ding et al., 2021; Li et al., 2021). A cross-sectional Chinese study analyzed menstrual data from 177 women of child-bearing age diagnosed with COVID-19 (Li et al., 2021). Twenty percent of these women presented with a significant decrease in menstrual volume, and 19% experienced a prolonged menstrual cycle. Severely ill patients had longer menstrual cycles than mildly ill patients. Follow-up data demonstrated that 99% of participants returned to their normal menstrual cycle length and 84% returned to a normal menstrual volume within 1–2 months after discharge. Blood samples from 91 women in this study were taken in the early follicular phase to test for sex hormones (follicle stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone) and anti-Mullerian hormone. There was no significant difference between sex hormone and anti-Mullerian hormone concentrations in the COVID-19 group when compared to agematched controls, suggesting that COVID-related menstrual disturbance may be a consequence of transient suppression of ovarian function (Li et al., 2021). A further Chinese study collected menstrual and biochemical data from 78 women with COVID-19 infection, and compared them with healthy agematched controls (Ding et al., 2021). In this study, there was no significant difference in menstrual status, menstrual volume, phase of menstrual cycle, and dysmenorrhea between women with non-severe and severe COVID19 infection. However, a significantly lower anti-Mullerian hormone level, along with higher serum testosterone and prolactin levels were observed in the COVID-19 group when compared with healthy controls and adjusted for potential confounders. This suggests that infection with COVID 19 may result in a reduction in ovarian reserve and abnormalities in reproductive hormones, although further large-scale longitudinal studies would be required to assess the validity and longer-term implications of this. Interestingly, women with polycystic ovarian syndrome were found in one UK study to have an increased risk

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of contracting Covid-19 infection when compared to age, BMI, and impaired glucose regulation controls (Subramanian et al., 2021). In conclusion, there are a number of potential pathological mechanisms through which SARS-CoV-2 infection may lead to menstrual disturbance. The available evidence suggests that there are associations between COVID19 illness, and both transient menstrual disturbance and diminished ovarian reserve. However, studies to date demonstrate conflicting results, were limited to small groups of women, and were conducted early in the pandemic. Further large-scale, longitudinal studies are required to explore the direct impact of SARS-CoV-2 infection on female reproductive health.

SARS-CoV-2 Infection in Pregnancy Infection during pregnancy has been shown to increase the risk of severe disease and preterm delivery. A Canadian study of over 6,000 COVID positive pregnancies showed that COVID infection increased the risk of intensive care unit admission and preterm birth (McClymont et al., 2022). Being pregnant was associated with a significantly increased risk of hospitalization compared with non-pregnant infected women. A systematic review showed pregnant women with COVID infection were more likely to deliver preterm and had an increased risk of maternal death and admission to intensive care, than pregnant women without COVID (Allotey et al., 2020). One Scottish prospective cohort study showed 77% of COVID infections in pregnancy were in unvaccinated women and 98% of pregnant women admitted to intensive care for COVID infection were unvaccinated (Stock et al., 2022). Vaccination has been shown to be protective, and encouraging vaccination in pregnancy is vitally importance in this at-risk cohort.

Impact of SARS-CoV-2 Vaccination on Menstrual Cycles The impact of SARS-CoV-2 vaccination on menstruation has been studied across multiple studies using self-reported menstrual cycle data. Available research shows changes in menstrual cycle after COVID-19 vaccination are common but transient. The etiology of menstrual cycle disturbance related to vaccination is unclear. Vaccine hesitancy in young women has been in part driven by false and misleading claims that the vaccine may decrease fertility (Sherman et al., 2022). Studies have shown no association between vaccines and infertility (Hillson et al., 2021). Over 50,000 suspected COVID-19 vaccination reactions relating to menstrual changes have been reported to the UK Medicines and Healthcare products Regulatory Agency’s Yellow Card Scheme thus far (GOV.UK, 2022). The nature of this reporting is that these events are reported as suspected, but not proven, side effects of vaccination. The most common disorders or changes reported were heavier than usual bleeding, delayed periods, and unexpected vaginal bleeding. These menstrual changes were mostly transient in nature.

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One prospective study that tracked menstrual cycle data using the application “Natural Cycles” and included 3,959 women aged 18–45 years in the US showed a small change in cycle length but not menses length post-vaccination (Edelman et al., 2022). Of these women, 2,403 were vaccinated, and the remainder acted as a “control group.” The first dose of vaccine had no effect on timing of the subsequent period, while the second dose was associated with a delay of 0.45 days. The women most affected were those who had received both doses of the vaccine in the same cycle, whose next period was delayed by median 2.32 days. Cycle length normalized within two cycles after vaccination for all groups. A similar Norwegian study used mobile phone questionnaires to collect retrospective data on menstrual disturbance in 5,688 women before and after COVID-19 vaccination (Trogstad, 2022). This study found that the prevalence of menstrual disturbance prior to vaccination was 37.8% among its participants, highlighting the high level of normal variation. After both doses of vaccine women reported heavier bleeding than usual. A large Spanish study of 14,153 women who had received a full course of COVID-19 vaccination showed 78% of women reported menstrual cycle changes post-vaccination (BaenaGarcía et al., 2022). The most reported menstrual cycle changes were increased menstrual bleeding (43%), increased menstrual pain (41%), delayed menstruation (38%), fewer days of bleeding (34.5%), and shorter length of cycle (32%). Further studies are needed to investigate immunological influences on menstruation and better understand the mechanisms behind these menstrual changes, and also to assess if any particular groups of women are more vulnerable to these changes, for example those with underlying benign gynecological conditions.

The Impact of the COVID-19 Pandemic and Mitigation Measures on Female Reproductive Health In this section, we review the current literature on female reproductive health during the COVID-19 pandemic period. Reports have demonstrated an association between complex social crises (e.g. war, natural disasters) and disturbance of menstrual and sexual function in the context of psychological distress (Hannoun et al., 2007; Liu et al., 2010). Available evidence suggests that there may be an association between the COVID-19 pandemic and changes in menstrual patterns and sexual behaviors. Several studies of varying quality have reported on menstrual cycle features during the COVID-19 pandemic. Most of these studies suggest that women have experienced menstrual cycle disruption since the beginning of the pandemic. A cross-sectional online survey-based study completed by over 17,000 women of reproductive age in Spain reported menstrual alterations in 39% of women since the onset of the pandemic (Medina-Perucha et al., 2022). Reported changes included dysmenorrhea (13%), longer (13%) and shorter menstrual cycles (10%), increased menstrual bleeding (7%), missed periods

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(7%), longer menses (6%), shorter menses (5%), and decreased menstrual bleeding (5%). Menstrual cycle disturbance was reported by those who had and had not contracted COVID-19 infection. Among participants with no history of COVID-19 infection, factors which significantly increased the odds of menstrual disturbance included experiencing financial strain and poorer self-perceived health. Indeed, stress exerts multiple inhibitory effects on the hypothalamic pituitary gonadal axis, primarily through activation of the hypothalamic pituitary adrenal axis (Chrousos et al., 1998; Mayerhofer et al., 1997; Vermeulen, 1993). The vulnerability of the female hypothalamic pituitary adrenal axis to psychosocial stress is a key consideration when evaluating the effects of the COVID-19 pandemic on the menstrual cycle. Two cross-sectional survey-based studies were conducted in Ireland in September 2020 and April 2021, each including data from over 1,000 women (Maher et al., 2022; Phelan et al., 2021). Their findings demonstrate that 46% and 56% of women respectively reported an overall change in their menstrual cycle since the beginning of the pandemic. In addition, they demonstrate wider variability in minimum and maximum menstrual cycle length, along with increases in self-reported heavy menstrual bleeding, dysmenorrhea, missed periods, and pre-menstrual symptoms compared to pre-pandemic. The latter study employs standardized measures of depression, anxiety, and sleep quality as a means of examining the relationship between mental health and menstrual changes (Maher et al., 2022). The authors show that poor sleep quality was an independent predictor of overall change in menstrual cycle and missed periods during the pandemic, whilst increased anxiety was independently associated with change from non-painful to painful periods and worsening of pre-menstrual symptoms during the pandemic. Again, these studies suggest that menstrual disturbance may be attributable to the burden of psychological distress stemming from the pandemic. However, it is important to consider that menstrual disturbance may also relate to metabolic stressors. Obesity is associated with oligomenorrhoea and heavy menstrual flow (De Pergola et al., 2009; Hartz et al., 1979), and over half of survey respondents reported a worsening of their diet and weight gain since the beginning of the pandemic. A study conducted in Turkey incorporated data from 952 female healthcare providers and found that depression, anxiety, and stress were positively correlated with irregular menstrual cycles (Takmaz et al., 2021). A further study carried out in Indonesia in the early stages of the pandemic found that an unspecified menstrual change occurred in 32% of 110 women surveyed and this was significantly correlated to psychological distress (Prabowo et al., 2022). In a retrospective observational study using data from a fertility tracking device including 13,194 menstrual cycles from 1,159 women living in 15 countries, menstrual cycle indicators changed only slightly in the first 6 months of 2020, as compared to 2019, but were still statistically significant (Haile et al., 2022). Menstrual cycle analysis found that average days of menses was longer, whilst average cycle length and pre-ovulation phase

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length were shorter. On the contrary, there are some studies which report that the COVID-19 pandemic has not led to menstrual disturbance. A retrospective cohort study which examined raw data from over 18,000 women using a menstrual tracking smartphone app did not show any evidence of population-level changes to ovulation and menstruation when comparing data between March–September 2019 and March–September 2020 (B. T. Nguyen et al., 2021). While this study limits recall bias associated with many of the other studies, it was carried out early in the pandemic. Additionally, most women in this study were over the age of 30 years, highly educated, and from high-income countries. Irregular menstruation has previously been found to be associated with lower educational and socioeconomic status (Kwak et al., 2019). In conclusion, research to-date suggests that many women have experienced changes to their menstrual cycle during the COVID-19 pandemic, and this is associated with psychological stress. However, there are several limitations which must be considered when interpreting the findings of the current studies. It is possible that observed associations between the pandemic and menstrual cycles could be due to various types of bias which limit the study of true causal effects (Sharp et al., 2021). Most of these studies rely on self-reported data which is vulnerable to reporting bias. Indeed, self-reporting of menstrual cycle length has been shown to have measurement error (Small et al., 2007). Survey-based studies may also be subject to sampling biases, where those who decided to complete the survey were those who were more likely to have experienced menstrual disturbance. Moreover, it is difficult to establish causality within small-scale studies as a result of the complex and multidirectional relationships between pandemic-related exposures (e.g. mitigation strategies, COVID-19 infection/vaccination), mental health outcomes, and menstrual disturbance (Sharp et al., 2021; Toufexis et al., 2014). Finally, there is a large degree of heterogeneity between current studies in terms of the study population and methods employed to assess menstrual disturbance and psychological distress. For example, social inequities in experiencing menstrual aberrations need to be considered prior to extrapolation of results to the global population, given the varied impact of the pandemic on menstrual patterns by sociodemographic characteristics (Medina-Perucha et al., 2022). Further research is imperative to establish the nature and scale of pandemicrelated menstrual cycle changes. Studies that minimize reporting and sampling bias, control for key confounders, and use standardized assessments of menstrual cycle features and mental health are required (Sharp et al., 2021). In addition, the social background of the study population should be described including the prevailing pandemic mitigation measures, incidence of COVID-19 infection, awareness of menstrual health, and availability of reproductive health services. Further longitudinal studies may be conducted by collecting interval data on menstrual cycle changes within existing cohort studies, in conjunction with the use of menstrual tracking mobile apps. Further characterization of the extent, origins, and impact of menstrual cycle disturbance will facilitate the

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identification of new preventative and therapeutic strategies and may be used to inform global public health policy. Several studies have investigated changes in sexual desire and frequency of sexual intercourse in parallel with the assessment of menstrual cycle changes (Maher et al., 2022; Phelan et al., 2021; Prabowo et al., 2022; Yuksel & Ozgor, 2020). Available evidence suggests that the COVID-19 pandemic has had an overall negative impact on female sexual function. Fifty-four percent of 1,335 women surveyed in Ireland reported a decrease in their libido over the course of the pandemic (Maher et al., 2022). This effect was amplified when compared to 45% of 1,031 women who reported reduced libido in a similar study earlier in the pandemic (Phelan et al., 2021). Selfreported reduced sexual desire is associated with decrements in health-related quality of life and negative emotional states, including poor self-esteem and hopelessness (Goldstein et al., 2017; Leiblum et al., 2006). In the later study, superior levels of physical and mental health-related quality of life were shown to be protective against worsening libido. An observational study conducted in Italy further illustrates the negative impact of the pandemic on female sexual function, with decreases in frequency of sexual intercourse and female sexual function index scores, along with an increase in female sexual distress scale scores observed in association with reduced quality of life (Schiavi et al., 2020). A cross-sectional study of 58 women carried out in Turkey reported a decrease in quality of sexual life, despite increased sexual desire and frequency of sexual intercourse compared with 6–12 months prior to the pandemic (Yuksel & Ozgor, 2020). This study also demonstrates that there was a marked decline in women intending to become pregnant due to the pandemic. The authors hypothesized that this was due to the perceived possible effects of the virus on the fetus along with economic concerns since most of their study population were from low to middle socioeconomic class. Another survey carried out in the early stages of the pandemic surveyed 348 Indonesian women and showed that 53% of their population did not change their desire to have children during the COVID-19 pandemic (Prabowo et al., 2022). However, this cohort may have had fewer financial concerns as they were mostly of middle to high socioeconomic status. This study also demonstrated that frequency of sexual intercourse during the pandemic significantly decreased. They postulate that contrasting changes in frequency of sexual intercourse between different studies may relate to differing cultural and social norms between countries. A study conducted in Italy, which is a less conservative country than Turkey and Indonesia, showed that 51% of non-cohabiting/ single women discontinued short-acting reversible contraception but 47% of them continued their sexual activity, causing a rise in unplanned pregnancies (Caruso et al., 2020). In conclusion, although existing research demonstrates considerable variability in change in women’s sexual behavior, the pandemic appears to have had many unfavorable effects. Ongoing research is necessary to explore this

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issue seen as many of the existing studies were conducted in the early stages of the pandemic. Many studies report a decline in female contraceptive use over the course of the COVID-19 pandemic (Caruso et al., 2020; Lewis et al., 2021; Miller et al., 2021; Prabowo et al., 2022; Steenland et al., 2021; Yuksel & Ozgor, 2020). A nationwide study of US health insurance claims found significant decline in contraceptive visits at the onset of the COVID-19 pandemic (Steenland et al., 2021). When visits in December 2020 were compared with December 2019, the sustained change in visits was greater for tubal ligation and injectable contraception visits than for long-acting reversible contraceptives and pill, patch, and ring visits. Tubal ligation saw the largest decline as it is a hospital-based procedure and patients are required to sign a written consent form 30 days prior (Evans et al., 2021). On the contrary, telehealth proved useful for the ongoing provision of the contraceptive pill, patch, and ring. Smaller cross-sectional studies have also shown a decrease in female contraceptive use in different populations during the COVID-19 pandemic. A study conducted in Turkey including data from 58 women demonstrated decreased female contraception use compared with prior to the pandemic (Yuksel & Ozgor, 2020). A survey of 348 women in Indonesia demonstrated a contraception prevalence rate of 23% compared to 44% in a representative pre-pandemic sample (Prabowo et al., 2022). An online survey conducted in the UK showed that COVID-19-related service inhibited young people’s access to free condoms and contraception during the early stages of the pandemic (Lewis et al., 2021). Furthermore, the pandemic may have disproportionally affected non-cohabiting or single females’ contraceptive practices as they may be more inclined to cease shortacting reversible contraception of their own volition, than married/cohabiting females, while social distancing (Caruso et al., 2020). In summary, research to-date suggests an overall decline in female contraceptive use during the COVID-19 pandemic, likely attributable to a combination of pandemic-related healthcare disruptions and changes to sexual behavior as a result of social distancing.

Female Reproductive Health in Long COVID Female reproductive health in Long COVID remains an understudied area, despite the fact that female sex and age under 50 years are recognized risk factors for Long COVID (Sigfrid et al., 2021). Available research suggests that a significant proportion of women affected by Long COVID experience menstrual cycle disruption. An international survey-based study in which participants had confirmed or suspected COVID-19 with illness lasting over 28 days included data from 1,792 women with a menstrual cycle (Davis et al., 2021), of which 36% reported nonspecific menstrual disturbance. More specifically, 26% reported abnormally irregular menstrual cycles and 20% reported abnormally heavy

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menses. Of 1,124 women aged over 49 years, 5% experienced postmenopausal bleeding/spotting, and of 938 women aged in their 40s, 3% reported early menopause. A cross-sectional study conducted in Jordan and Iraq demonstrated a wide range of menstrual changes in a sample of 483 women who had been previously infected with COVID-19 (Al-Najjar et al., 2022). Amongst this cohort, 47% suffered from a change in the duration of their menstrual cycle, 47% reported a change in menstrual blood loss, and 42% reported an increase or decrease in the length of menses. A study carried out in the United Kingdom found that 50% of 460 women surveyed reported that their menstrual period had stopped or changed since experiencing COVID-19 infection (Newson et al., 2021). In parallel, 62% of these women felt that their symptoms of Long COVID were increased on the days before their menstrual period, at the time of nadir estrogen levels. This indicates that the wider symptoms of Long COVID may be partly mediated by disturbance of physiological ovarian steroid hormone production (Newson et al., 2021; Stewart et al., 2021). There is limited literature describing the effect of other post-viral illnesses on female reproductive health. Women with myalgic encephalomyelitis/chronic fatigue syndrome, which can present similar to Long COVID, may report increased rates of heavy menstrual bleeding, intermenstrual bleeding, and endometriosis compared to healthy controls (Boneva et al., 2015). Previous observational research indicates that a minority of women with acute COVID-19 infection experience transient menstrual changes (Li et al., 2021). This is hypothesized to occur due to expression of the ACE2 receptor in the ovaries, through which SARS CoV-2 gains cellular access, with resultant suppression of ovarian function (Li et al., 2021; Zhang et al., 2020). Disruption of ovarian steroid hormone production in this manner could potentiate symptoms of perimenopause/menopause (Stewart et al., 2021). Furthermore, symptoms of Long COVID and perimenopause/menopause (fatigue, myalgia, cognitive disturbance, sleep disturbance) may overlap creating diagnostic uncertainty. Indeed, up to 70% of women may attribute some of their Long COVID symptoms to either perimenopause or menopause (Newson et al., 2021) or vice versa. Failure to appropriately diagnose perimenopause and menopause misses an opportunity to manage the immediate symptoms with hormone replacement therapy, but also to employ additional measures to mitigate the risk of cardiovascular disease, osteoporosis, and dementia (Stewart et al., 2021). It is critical to progress the awareness and education of both the general female population and physicians around the potential overlap of Long COVID and perimenopausal/menopausal symptoms such that appropriate management strategies can be instigated. In conclusion, there appears to be an association between Long COVID and menstrual cycle disturbance. In addition, it may be difficult to differentiate between the wider symptoms of Long COVID and perimenopause, resulting in suboptimal treatment. Further research is imperative to explore the links between Long COVID and the female reproductive axis.

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Clinical Approach to Menstrual Cycle Abnormalities in the Era of the COVID-19 Pandemic Given the overall lack of longitudinal, population-level data and the bias in the existing data, as well as the barriers to carrying out this research, it is difficult to make evidence-based recommendations to clinicians who see women with reproductive health disturbance in the era of the COVID-19 pandemic. There are no studies which assess interventions for women presenting with menstrual cycle disturbance in this setting, nor is there published guidance. The authors therefore advocate a thorough clinical assessment incorporating physical, psychological, hormonal, and lifestyle assessment. With regards to the impact of COVID-19 vaccination on reproductive health, however, it is clear from studies that menstrual cycle changes may occur, but are usually mild and transient. Women deserve accurate information about the impact of any medical intervention on their reproductive health. We therefore suggest that those administering vaccines to women should include the following in their discussions of risks and benefits: • •

• •

Menstrual cycle changes may occur after COVID-19 vaccination. Cycle length may be longer, or bleeding may be heavier; however changes are mild and short lived, lasting usually for one to two cycles. Temporary disruption to cycles is a much lower risk to overall health than the potential impact of COVID-19 infection, especially in women of reproductive age, as severe disease can be harmful to pregnant women and their babies. There is no evidence that fertility or pregnancy outcomes are impacted by vaccination. Women who are concerned about their menstrual cycles after the vaccination should seek advice from their doctor, as they may have other features suggestive of an underlying reproductive health condition.

Women may present to healthcare workers for the first time with underlying reproductive health conditions which may be contemporaneously attributed to COVID-19 infection or Long COVID due to the high prevalence of both. In addition, certain conditions may have worsened over the course of the pandemic. Women, some with polycystic ovary syndrome, for example, have experienced worsening symptoms of the condition during the pandemic due to weight gain, psychological distress, reduced access to healthcare, and cosmetic services (Maher et al., unpublished). Functional hypothalamic amenorrhea may also be more prevalent in response to the psychological impact of the pandemic, as some studies have shown an increased prevalence of missed periods during the pandemic (Maher et al., 2022; Phelan et al., 2021). There has been significant media coverage of the impact of the pandemic and vaccination on reproductive health, so women may present for the first time with benign gynecological conditions, due to the spotlight that has been shone on this area over the last couple of years.

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It is important therefore not to assign causality to COVID-19 or long COVID without assessment for an alternate underlying cause. For those women reporting persistent menstrual cycle disturbance, we recommend a thorough assessment of signs and symptoms of common benign gynecological conditions, such as polycystic ovary syndrome (irregular periods, acne, excess hair, scalp hair loss, weight gain, anxiety, and depression) and endometriosis (painful periods, pelvic pain, heavy menstrual bleeding, pain during intercourse). We recommend assessing for menopausal symptoms (hot flushes, brain fog, mood swings, insomnia, loss of libido, vaginal dryness). For those with persistent cycle changes we recommend measuring weight and body mass index and completing blood tests, the choice of which will depend on predominant features, e.g. gonadotropins, estradiol, prolactin, free testosterone, thyroid function. Menstrual cycle changes may also be related to change in or discontinuation of hormonal contraception, as multiple studies have shown a reduction in contraception use during the pandemic. We also therefore recommend assessment of contraceptive use and using this opportunity to counsel women regarding sexual health and contraception. With regards to those women reporting menstrual cycle disturbance after having COVID-19 infection which has not persisted for three or more cycles, if cycles have returned to normal we recommend reassurance that changes were transient and unlikely to impact long-term reproductive health. For women with short-term cycle disturbance which is ongoing but for less than three cycles, they should continue to track their menstrual cycles and monitor for persistent disruption. For those women reporting persistent cycle disturbance without features of an obvious underlying biological cause, we recommend considering baseline blood tests as outlined above, as well as an assessment of psychological health. Studies have shown that menstrual cycle changes associated with the COVID-19 pandemic are correlated with mental health test scores. Therefore we recommend assessment of mental health, utilizing validated scores and as recommended by local guidelines. Treatment should also be based on local guidance. Cognitive behavioral therapy can be effective in certain conditions such as polycystic ovary syndrome, menopause, and functional hypothalamic amenorrhea. Advising women about lifestyle changes may also be beneficial, for example weight loss in polycystic ovary syndrome may restore ovulation and improve symptoms. Weight gain and adequate caloric intake may stimulate resumption of menses in hypothalamic amenorrhea. The symptoms of Long COVID may partly be due to alterations in ovarian steroid hormone production and/or an altered gender specific immunomodulation. Further research is required to assess this. Also, due to overlap in symptoms (e.g. fatigue, brain fog), many perimenopausal women may be misdiagnosed with Long COVID. We therefore recommend that those providing care for or assessing women with Long COVID who are at or approaching the age of menopause should ask them about symptoms of menopause, which may be ultimately contributing to or causing their symptoms.

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Conclusions Available evidence suggests that the COVID-19 pandemic and mitigation measures have impacted women’s menstrual cycles, resulting in changes in cycle duration, heavy menstrual bleeding, missed periods, and worsening pre-menstrual symptoms. These changes appear to be related in part to psychological disturbance. This menstrual disruption may be transient; however longitudinal data has not been published. The pandemic, at least initially, has been associated with reduced use of contraceptives. Studies have also shown reduced libido and frequency of sexual activity. The impact of all of this on fecundity is thus far unknown and is likely to vary depending on geographical location. Future research should study the following areas, using large-scale, longitudinal studies in varied populations; firstly, the long-term effects of exposure to SARS-CoV-2 and pandemic mitigation measures on reproductive health and fertility and secondly the tools that could be used to recognize, modify, and treat/reverse the negative impact on reproductive health.

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228  Menstrual Cycle and Reproductive Health Caruso, S., Rapisarda, A. M. C., & Minona, P. (2020). Sexual activity and contraceptive use during social distancing and self-isolation in the COVID-19 pandemic. European Journal of Contraception & Reproductive Health Care, 25(6), 445–448. https://doi​.org​/10​ .1080​/13625187​.2020​.1830965 Cerrato, J., & Cifre, E. (2018). Gender inequality in household chores and work-family conflict. Frontiers in Psychology, 9, 1330. https://doi​.org​/10​.3389​/fpsyg​.2018​.01330 Chadchan, S. B., Popli, P., Maurya, V. K., & Kommagani, R. (2021). The SARS-CoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization. Biology of Reproduction, 104(2), 336–343. Chrousos, G. P., Torpy, D. J., & Gold, P. W. (1998). Interactions between the hypothalamicpituitary-adrenal axis and the female reproductive system: Clinical implications. Annals of Internal Medicine, 129(3), 229–240. Davies, J., & Kadir, R. A. (2012). Endometrial haemostasis and menstruation. Reviews in Endocrine and Metabolic Disorders, 13(4), 289–299. Davis, H. E., Assaf, G. S., McCorkell, L., Wei, H., Low, R. J., Re'em, Y., Redfield, S., Austin, J. P., & Akrami, A. (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. eClinicalMedicine, 38, 101019. De Pergola, G., Tartagni, M., d’Angelo, F., Centoducati, C., Guida, P., & Giorgio, R. (2009). Abdominal fat accumulation, and not insulin resistance, is associated to oligomenorrhea in non-hyperandrogenic overweight/obese women. Journal of Endocrinological Investigation, 32(2), 98–101. Ding, T., Wang, T., Zhang, J., Cui, P., Chen, Z., Zhou, S., Yuan, S., Ma, W., Zhang, M., & Rong, Y. (2021). Analysis of ovarian injury associated with COVID-19 disease in reproductiveaged women in Wuhan, China: An observational study. Frontiers in Medicine, 286. Edelman, A., Boniface, E. R., Benhar, E., Han, L., Matteson, K. A., Favaro, C., Pearson, J. T., & Darney, B. G. (2022). Association between menstrual cycle length and coronavirus disease 2019 (COVID-19) vaccination: A U.S. Cohort. Obstetrics & Gynecology, 139(4), 481–489. https://doi​.org​/10​.1097​/AOG​.0000000000004695 Engzell, P., Frey, A., & Verhagen, M. D. (2021). Learning loss due to school closures during the COVID-19 pandemic. Proceedings of the National Academy of Sciences, 118(17). https://doi​.org​/10​.1073​/pnas​.2022376118 Evans, M. L., Qasba, N., & Arora, K. S. (2021). COVID-19 highlights the policy barriers and complexities of postpartum sterilization. Contraception, 103(1), 3–5. Fatimazahra, M., Harras, M. E., Bensahi, I., Kassimi, M., Oualim, S., Elouarradi, A., Abdeladim, S., & Sabry, M. (2021). Ovarian vein thrombosis after coronavirus disease (COVID-19) mimicking acute abdomen: Two case reports. Journal of Thrombosis and Thrombolysis, 52(2), 493–496. Goldstein, I., Kim, N. N., Clayton, A. H., DeRogatis, L. R., Giraldi, A., Parish, S. J., Pfaus, J., Simon, J. A., Kingsberg, S. A., Meston, C., Stahl, S. M., Wallen, K., & Worsley, R. (2017). Hypoactive sexual desire disorder: International Society for the Study of Women’s Sexual Health (ISSWSH) expert consensus panel review. Mayo Clinic Proceedings, 92(1), 114–128. doi: 10.1016/j.mayocp.2016.09.018. Epub 2016 Dec 1. PMID: 27916394. Haile, L., van de Roemer, N., Gemzell-Danielsson, K., Perelló Capó, J., Lete Lasa, I., Vannuccini, S., Koch, M. C., Hildebrandt, T., & Calaf, J. (2022). The global pandemic and changes in women’s reproductive health: An observational study. The European Journal of Contraception & Reproductive Health Care, 27(2), 102–106. Hannoun, A. B., Nassar, A. H., Usta, I. M., Zreik, T. G., & Abu Musa, A. A. (2007). Effect of war on the menstrual cycle. Obstetrics & Gynecology, 109(4), 929–932. https://doi​.org​ /10​.1097​/01​.AOG​.0000257170​.83920​.de

Menstrual Cycle and Reproductive Health  229 Hartz, A., Barboriak, P. N., Wong, A., Katayama, K. P., & Rimm, A. A. (1979). The association of obesity with infertility and related menstural abnormalities in women. International Journal of Obesity, 3(1), 57–73. Hillson, K., Clemens, S. C., Madhi, S. A., Voysey, M., Pollard, A. J., Minassian, A. M., & Group, O. C. V. T. (2021). Fertility rates and birth outcomes after ChAdOx1 nCoV19 (AZD1222) vaccination. Lancet, 398(10312), 1683–1684. https://doi​.org​/10​.1016​/ S0140​-6736(21)02282-0 Jacobs, M. B., Boynton-Jarrett, R. D., & Harville, E. W. (2015). Adverse childhood event experiences, fertility difficulties and menstrual cycle characteristics. Journal of Psychosomatic Obstetrics & Gynaecology, 36(2), 46–57. https://doi​.org​/10​.3109​/0167482X​.2015​.1026892 Kwak, Y., Kim, Y., & Baek, K. A. (2019). Prevalence of irregular menstruation according to socioeconomic status: A population-based nationwide cross-sectional study. PLoS One, 14(3), e0214071. Leiblum, S. R., Koochaki, P. E., Rodenberg, C. A., Barton, I. P., & Rosen, R. C. (2006). Hypoactive sexual desire disorder in postmenopausal women: US results from the Women's International Study of Health and Sexuality (WISHeS). Menopause, 13(1), 46–56. https://doi​.org​/10​.1097​/01​.gme​.0000172596​.76272​.06 Lewis, R., Blake, C., Shimonovich, M., Coia, N., Duffy, J., Kerr, Y., Wilson, J., Graham, C. A., & Mitchell, K. R. (2021). Disrupted prevention: Condom and contraception access and use among young adults during the initial months of the COVID-19 pandemic. An online survey. BMJ Sexual & Reproductive Health, 47(4), 269–276. Li, K., Chen, G., Hou, H., Liao, Q., Chen, J., Bai, H., Lee, S., Wang, C., Li, H., Cheng, L., & Ai, J. (2021). Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reproductive BioMedicine Online, 42(1), 260–267. https://doi​.org​/10​ .1016​/j​.rbmo​.2020​.09​.020 Liu, S., Han, J., Xiao, D., Ma, C., & Chen, B. (2010). A report on the reproductive health of women after the massive 2008 Wenchuan earthquake. International Journal of Gynecology & Obstetrics, 108(2), 161–164. Maher, M., O’ Keeffe, A., Phelan, N., Behan, L. A., Collier, S., Hevey, D., & Owens, L. (2022). Female reproductive health disturbance experienced during the COVID-19 pandemic correlates with mental health disturbance and sleep quality [original research]. Frontiers in Endocrinology, 13. https://doi​.org​/10​.3389​/fendo​.2022​.838886 Maity, S., Wray, J., Coffin, T., Nath, R., Nauhria, S., Sah, R., Waechter, R., & Ramdass, P. (2022). Academic and social impact of menstrual disturbances in female medical students: A systematic review and meta-analysis. Frontiers in Medicine, 9, 821908. https:// doi​.org​/10​.3389​/fmed​.2022​.821908 Malik, S., Day, K., Perrault, I., Charnock-Jones, D. S., & Smith, S. K. (2006). Reduced levels of VEGF-A and MMP-2 and MMP-9 activity and increased TNF-α in menstrual endometrium and effluent in women with menorrhagia. Human Reproduction, 21(8), 2158–2166. Maybin, J. A., & Critchley, H. O. (2015). Menstrual physiology: Implications for endometrial pathology and beyond. Human Reproduction Update, 21(6), 748–761. Maybin, J. A., Murray, A. A., Saunders, P. T., Hirani, N., Carmeliet, P., & Critchley, H. O. (2018). Hypoxia and hypoxia inducible factor-1α are required for normal endometrial repair during menstruation. Nature Communications, 9(1), 1–13. Mayerhofer, A., Dissen, G. A., Costa, M. E., & Ojeda, S. R. (1997). A role for neurotransmitters in early follicular development: Induction of functional folliclestimulating hormone receptors in newly formed follicles of the rat ovary. Endocrinology, 138(8), 3320–3329.

230  Menstrual Cycle and Reproductive Health McClymont, E., Albert, A. Y., Alton, G. D., Boucoiran, I., Castillo, E., Fell, D. B., Kuret, V., Poliquin, V., Reeve, T., Scott, H., Sprague, A. E., Carson, G., Cassell, K., Crane, J., Elwood, C., Joynt, C., Murphy, P., Murphy-Kaulbeck, L., Saunders, S., . . . & Team, C.-P. (2022). Association of SARS-CoV-2 infection during pregnancy with maternal and perinatal outcomes. JAMA, 327(20), 1983–1991. https://doi​.org​/10​.1001​/jama​ .2022​.5906 McDade, T. W. (2005). The ecologies of human immune function. Annual Review of Anthropology, 34, 495. Medina-Perucha, L., López-Jiménez, T., Holst, A. S., Jacques-Aviñó, C., Munrós-Feliu, J., Martínez-Bueno, C., Valls-Llobet, C., Pinzón-Sanabria, D., Vicente-Hernández, M. M., & Berenguera, A. (2022). Self-reported menstrual alterations during the COVID-19 syndemic in Spain: A cross-sectional study. International Journal of Women's Health, 14, 529. Miller, H. E., Henkel, A., Leonard, S. A., Miller, S. E., Tran, L., Bianco, K., & Shaw, K. A. (2021). The impact of the COVID-19 pandemic on postpartum contraception planning. American Journal of Obstetrics & Gynecology MFM, 3(5), 100412. Newson, L., Lewis, R., & O'Hara, M. (2021). Long Covid and menopause-the important role of hormones in Long Covid must be considered. Maturitas, 152, 74. Nguyen, B. T., Pang, R. D., Nelson, A. L., Pearson, J. T., Benhar Noccioli, E., Reissner, H. R., Kraker von Schwarzenfeld, A., & Acuna, J. (2021). Detecting variations in ovulation and menstruation during the COVID-19 pandemic, using real-world mobile app data. PLoS One, 16(10), e0258314. Nguyen, N. T., Chinn, J., De Ferrante, M., Kirby, K. A., Hohmann, S. F., & Amin, A. (2021). Male gender is a predictor of higher mortality in hospitalized adults with COVID-19. PLoS One, 16(7), e0254066. https://doi​.org​/10​.1371​/journal​.pone​ .0254066 Phelan, N., Behan, L. A., & Owens, L. (2021). The impact of the COVID-19 pandemic on women's reproductive health. Frontiers in Endocrinology, 12, 642755. https://doi​.org​ /10​.3389​/fendo​.2021​.642755 Prabowo, K. A., Ellenzy, G., Wijaya, M. C., & Kloping, Y. P. (2022). Impact of work from home policy during the COVID-19 pandemic on mental health and reproductive health of women in Indonesia. International Journal of Sexual Health, 34(1), 17–26. Schiavi, M. C., Spina, V., Zullo, M. A., Colagiovanni, V., Luffarelli, P., Rago, R., & Palazzetti, P. (2020). Love in the time of COVID-19: Sexual function and quality of life analysis during the social distancing measures in a group of Italian reproductive-age women. Journal of Sexual Medicine, 17(8), 1407–1413. https://doi​.org​/10​.1016​/j​.jsxm​ .2020​.06​.006 Sharp, G. C., Fraser, A., Sawyer, G., Kountourides, G., Easey, K. E., Ford, G., Olszewska, Z., Howe, L. D., Lawlor, D. A., & Alvergne, A. (2021). The COVID-19 pandemic and the menstrual cycle: Research gaps and opportunities. International Journal of Epidemiology. Sharp, G. C., Fraser, A., Sawyer, G., Kountourides, G., Easey, K. E., Ford, G., Olszewska, Z., Howe, L. D., Lawlor, D. A., Alvergne, A., & Maybin, J. A. (2022). The COVID-19 pandemic and the menstrual cycle: Research gaps and opportunities. International Journal of Epidemiology, 51(3), 691–700. doi: 10.1093/ije/dyab239. PMID: 34865021; PMCID: PMC8690231. Sherman, S. M., Sim, J., Cutts, M., Dasch, H., Amlôt, R., Rubin, G. J., Sevdalis, N., & Smith, L. E. (2022). COVID-19 vaccination acceptability in the UK at the start of the vaccination programme: A nationally representative cross-sectional survey (CoVAccS wave 2). Public Health, 202, 1–9. https://doi​.org​/10​.1016​/j​.puhe​.2021​.10​.008 Sigfrid, L., Drake, T. M., Pauley, E., Jesudason, E. C., Olliaro, P., Lim, W. S., Gillesen, A., Berry, C., Lowe, D. J., McPeake, J., Lone, N., Munblit, D., Cevik, M., Casey, A., Bannister, P., Russell, C. D., Goodwin, L., Ho, A., Turtle, L., . . . & Scott, J. T. (2021).

Menstrual Cycle and Reproductive Health  231 Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO clinical characterisation protocol. The Lancet Regional Health - Europe, 8, 100186. https://doi​.org​/10​.1016​/j​.lanepe​.2021​.100186 Small, C. M., Manatunga, A. K., & Marcus, M. (2007). Validity of self-reported menstrual cycle length. Annals of Epidemiology, 17(3), 163–170. Steenland, M. W., Geiger, C. K., Chen, L., Rokicki, S., Gourevitch, R. A., Sinaiko, A. D., & Cohen, J. L. (2021). Declines in contraceptive visits in the United States during the COVID-19 pandemic. Contraception, 104(6), 593–599. Stewart, S., Newson, L., Briggs, T. A., Grammatopoulos, D., Young, L., & Gill, P. (2021). Long COVID risk-a signal to address sex hormones and women's health. The Lancet Regional Health – Europe, 11. Stock, S. J., Carruthers, J., Calvert, C., Denny, C., Donaghy, J., Goulding, A., Hopcroft, L. E. M., Hopkins, L., McLaughlin, T., Pan, J., Shi, T., Taylor, B., Agrawal, U., Auyeung, B., Katikireddi, S. V., McCowan, C., Murray, J., Simpson, C. R., Robertson, C., . . . & Wood, R. (2022). SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland. Nature Medicine, 28(3), 504–512. https://doi​.org​/10​.1038​ /s41591​-021​-01666-2 Subramanian, A., Anand, A., Adderley, N. J., Okoth, K., Toulis, K. A., Gokhale, K., Sainsbury, C., O'Reilly, M. W., Arlt, W., & Nirantharakumar, K. (2021). Increased COVID-19 infections in women with polycystic ovary syndrome: A population-based study. European Journal of Endocrinology, 184(5), 637–645. https://doi​.org​/10​.1530​/EJE​-20​-1163 Takmaz, T., Gundogmus, I., Okten, S. B., & Gunduz, A. (2021). The impact of COVID19-related mental health issues on menstrual cycle characteristics of female healthcare providers. Journal of Obstetrics and Gynaecology Research, 47(9), 3241–3249. Teuwen, L.-A., Geldhof, V., Pasut, A., & Carmeliet, P. (2020). COVID-19: The vasculature unleashed. Nature Reviews Immunology, 20(7), 389–391. Thomas, R., Cooper, M., Cardazone, G., Urban, K., Cardazone, G., Bohrer A., & Mahajan, S. (2021). Women in the Workplace 2020. McKinsey & Company. Toufexis, D., Rivarola, M. A., Lara, H., & Viau, V. (2014). Stress and the reproductive axis. Journal of Neuroendocrinology, 26(9), 573–586. Trogstad, L. (2022). Increased occurrence of menstrual disturbances in 18- to 30-year-old women after COVID-19 vaccination. Available at SSRN 3998180. Uguz, F., Sahingoz, M., Kose, S. A., Ozbebit, O., Sengul, C., Selvi, Y., Sengul, C. B., Ayhan, M. G., Dagistanli, A., & Askin, R. (2012). Antidepressants and menstruation disorders in women: A cross-sectional study in three centers. General Hospital Psychiatry, 34(5), 529–533. https://doi​.org​/10​.1016​/j​.genhosppsych​.2012​.03​.014 Vermeulen, A. (1993). Environment, human reproduction, menopause, and andropause. Environmental Health Perspectives, 101(suppl 2), 91–100. Yuksel, B., & Ozgor, F. (2020). Effect of the COVID-19 pandemic on female sexual behavior. International Journal of Gynaecology & Obstetrics, 150(1), 98–102. https://doi​.org​ /10​.1002​/ijgo​.13193 Zhang, H., Penninger, J. M., Li, Y., Zhong, N., & Slutsky, A. S. (2020). Angiotensinconverting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Medicine, 46(4), 586–590. https://doi​.org​/10​ .1007​/s00134​-020​-05985-9 Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H., & Cao, B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID19 in Wuhan, China: A retrospective cohort study. Lancet, 395(10229), 1054–1062. https://doi​.org​/10​.1016​/S0140​-6736(20)30566-3

14 Pediatric Issues Christine A. Capone, MD, MPH, Annabelle Quizon, MD, Elizabeth C. Mitchell, MD, and Maria Teresa Santiago, MD

The acute manifestations of SARS-CoV-2 infection in children have been extensively described. However, long-term outcomes and the risk of persistent symptoms (i.e., “Long COVID”) are poorly understood. In this chapter, we first briefly review the acute manifestations and subsequent complications of SARS-CoV-2 infection in children, as it is important to rule out residual injury prior to diagnosing Long COVID. We then focus on reviewing the existing literature on Long COVID and provide recommendations for monitoring and managing these pediatric patients.

Acute COVID/MIS-C Children with SARS-CoV-2 often have asymptomatic or mild disease. However, a minority of pediatric patients have a more severe course manifesting as acute respiratory distress syndrome (ARDS) and/or myocarditis, or 4–6 weeks later as a post-inflammatory disorder known as multi-system inflammatory syndrome in children (MIS-C). The acute presentation of MIS-C is defined by the Centers for Disease Control (CDC) as fever and laboratory evidence of inflammation in individuals under 21 years of age hospitalized for clinically severe illness involving 2 or more organ systems with no alternative diagnosis and who have been exposed to or tested positive for SARS-CoV-2 (PCR, serology, or antigen). In one of the larger multicenter studies describing this disease, 92% of children had gastrointestinal manifestations, 80% had cardiac involvement, 76% had hematologic abnormalities, 74% had rash and/ or mucocutaneous findings, and 70% had respiratory symptoms (Feldstein et al., 2020). In addition to multiple complaints, children with MIS-C have severe illness, with approximately 80% of patients requiring intensive care, 45–76% requiring vasoactive agents, 50% showing features of left ventricular (LV) systolic dysfunction and clinical myocarditis, 10–20% developing acute coronary artery aneurysms, 20% with EKG abnormalities/arrythmias, and 4%

DOI: 10.4324/9781003371090-14

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requiring extracorporeal membrane oxygenation (ECMO) (Feldstein et al., 2020; Capone et al., 2020; Fremed and Farooqi, 2022). There are no comparative studies evaluating the treatment protocols of MIS-C to date. Mainstays of treatment include steroids and IVIG with the addition of anakinra, an IL-1 inhibitor, in severe cases. Aspirin is also a mainstay treatment given the high incidence of coronary abnormalities. Enoxaparin is commonly used when thrombotic profiles are abnormal and/or when there is concern for coronary artery involvement. Multicentered studies have suggested that initial treatment with IVIG plus glucocorticoids was associated with a lower rate of treatment failure and a lower risk of new or persistent cardiovascular dysfunction than IVIG alone (Ouldali et al., 2021; Son et al., 2021). Expert recommendations and institutional treatment guidelines have been published by Capone et al. (2021), Henderson et al. (2022), and Dove et al. (2021). Long-term side effects of these medications are poorly understood. Fortunately, despite the severity of initial presentation, most abnormalities appear to quickly resolve within the first few weeks, supporting the notion that post-infectious conditions are the result of a hyperinflammatory response. A multicentered US study of 503 patients showed that 91% had normalized their LV systolic function and 100% had normalized their coronary aneurysms by 30 days, and that all had normal LV systolic function by 5 months (Feldstein et al., 2021). Farooqi et al. (2021) followed 45 patients through 9 months, and only 1 patient had persistent mild LV dysfunction. In both Penner et al. (2021) and Davies et al. (2021), all patients in the studies normalized their LV function and biomarkers, though one patient in each study continued to have a large coronary aneurysm at 6 months. Capone et al. (2021) followed 50 patients through 6 months from hospitalization and showed that 69% normalized their LV systolic function within a week and that all patients had normal LV systolic function and coronary arteries by 6 months. Cardiac MRI in the convalescent phase of 18 patients with clinical myocarditis was normal. Of note, one patient had persistent LV diastolic dysfunction at 6 months. Other studies also have reported that subclinical myocardial diastolic dysfunction and impaired global longitudinal strain persisted until 3 months, despite normalization of LV systolic function (Matsubara et al., 2022; Kobayashi et al., 2021). In addition, despite clinically presenting with a myocarditis-like picture, findings on cardiac magnetic resonance imaging (CMRI) that are consistent with viral myocarditis such as myocardial necrosis or fibrosis are rare. These studies highlight that residual cardiac injury, though rare, exists and needs to be ruled out as the cause of Long COVID symptoms. Scheduled outpatient cardiology follow-up with EKG, echocardiogram, and the Holter, stress test, or cardiac MRIs as clinically indicated will be important to differentiate between a complication of MIS-C versus a manifestation of Long COVID. Pulmonary fibrosis has been described as a sequela of ARDS (Burnham et al., 2014; Marshall et al., 1998; Spagnolo et al., 2020). Amongst adults, a substantial number of hospitalized patients with COVID-19 progress to ARDS, which is associated with higher odds of mortality. Epithelial cell injury triggers

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fibroproliferative pathways (Wijsenbeek and Cottin, 2020). The SARS-CoV-2 virus has been shown to have high infectivity in type II alveolar cells, which relates to their expression of the ACE-2 receptor (Sungnak et al., 2020). Type II alveolar cells are responsible for surfactant production and reepithelialization of the bronchoalveolar epithelium after injury, and are crucial in understanding the progression of COVID-19 to ARDS. Aside from epithelial injury, endothelial injury relates to pulmonary edema, development of thrombotic disease, and vascular damage. Vascular changes including microvascular leak and increased endothelial permeability are invoked in chronic fibrosing lung diseases such as pulmonary fibrosis (Probst et al., 2020). Direct cytotoxicity to the epithelium and endothelium eventually leads to the deposition of extracellular matrix by fibroblasts (Michalski et al., 2022). It is unknown whether full recovery from ARDS related to COVID-19 confers better prognosis and less likelihood of developing pulmonary fibrosis. Moreover, it is unknown whether patients with existing comorbidities, especially those with chronic lung diseases, have greater propensity for pulmonary fibrosis even as they experience greater functional impairment during recovery from COVID-19. On the other hand, autopsy studies from patients who died of COVID-19 showed findings of fibrotic lung disease such as traction bronchiectasis, interstitial fibrosis, and honeycombing (Grillo et al., 2021; Schwensen et al., 2021). Clinical, radiographic, and physiological (i.e., pulmonary function testing) follow-up studies are needed to understand the evolution and treatment of post-COVID pulmonary fibrosis as well as to help differentiate this complication from Long COVID. Before establishing a probable diagnosis of post-COVID syndrome, a differential diagnosis of other post-COVID conditions should be made to identify cardiopulmonary sequelae, post-COVID thrombosis, and post-COVID immune mediated manifestations. Cardiopulmonary sequelae include postpneumonia interstitial involvement, pleural thickening or effusion, and cardiac involvement such as myocarditis and pericardial effusion. The main postCOVID immune manifestations include arthritis, myositis with elevated creatine kinase levels, and pancreatitis (Siso-Amiral et al., 2021). The focus of this review, however, is on children with Long COVID who do not have intrinsic abnormalities and present with symptoms with no alternative diagnosis.

Long COVID Chronic health impairments have emerged as a long-term complication after SARS-CoV-2 infection in adults and have been called “Long COVID” or “post-acute sequelae of SARS-CoV-2” (PASC). However, our current understanding of the clinical presentation of this disorder in children is limited. Definitions from the WHO, NICE, and CDC are described in Chapter 1 of this book; these definitions are based on adult data and may not be applicable to children. Available data on Long COVID in children is hindered by a lack of a uniform definition, including characteristics required for diagnosis and the

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Figure 14.1 The pooled prevalence of Long COVID by symptoms in children and adolescents. The overall presence of one or more symptoms following SARSCoV-2 infection was 25.24% Reprinted with permission from Lopez-Leon et al. (2022).

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duration they must be present, which has resulted in marked heterogeneity between studies and a wide variability of prevalence estimates (Zimmerman et al., 2021). As a result, prevalence estimates have ranged from 2 to 66% (Zimmerman et al., 2021; Rao et al., 2022) and can vary depending on severity of infection and if patients presented with acute COVID versus MIS-C. The estimated pooled prevalence of Long COVID in children is around 25% overall and around 29% for hospitalized patients based on the most recent meta-analysis including observational studies of over 80,000 children (Lopez-Leon et al., 2022). When comparing Long COVID symptoms in children who tested positive for SARS-CoV-2 compared to controls, the overall incidence of Long COVID may be closer to 4% (Rao et al., 2022). This incidence is from a pooled study of outpatient and acutely hospitalized patients which excluded MIS-C. Looking at Long COVID in non-hospitalized patients alone, the reported incidence is ~2% (Molteni et al., 2021). When comparing the incidence in hospitalized children, a recent multicentered prospective study found persistent symptoms 2–4 months from hospitalization in 26.9% of children hospitalized with acute COVID and 30% of children hospitalized with MIS-C (Maddux et al., 2022). The available data indicates that the prevalence of Long COVID in children is lower than in adults. Regardless of whether children have asymptomatic, mild, or severe infection requiring hospitalization, a subset of pediatric patients experience chronic health impairments which pediatric providers must be aware of and screen for. There are more than 40 symptoms attributed to Long COVID in children. The most common are mood symptoms (16.50%), fatigue (9.66%), sleep disorders (8.42%), headache (7.84%), respiratory symptoms (7.62%), orthostatic intolerance (6.92%), and exercise intolerance (5.73%) (LopezLeon et al., 2022). Long COVID in children should be suspected in the presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia, and arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should also be considered as possible symptoms of Long COVID (Esposito et al., 2022). Figure 14.1 shows the type and the prevalence of symptoms in Long COVID. Features such as fatigue, chest pain, cardiorespiratory symptoms, fever, and loss of taste/smell overlap in adults and children with Long COVID symptoms. However, features such as abnormal liver enzymes, hair loss, skin rashes, and diarrhea may be more common in children than in adults (Rao et al., 2022).

Risk Factors Long COVID symptoms in children may be independent of the severity of the initial infection and occur despite resolution of laboratory and echocardiographic abnormalities (Maddux et al., 2022; Townsend et al., 2020; Petracek et al., 2021). Patients with both mild and moderate-severe disease

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have been reported to develop Long COVID. Risk factors for the development of Long COVID in children are not as well characterized as in adults. In adults, older age, female gender, hospital admission at symptom onset, initial dyspnea, chest pain, abnormal auscultation findings, symptom load during acute phase of illness, overweight/obesity, and pre-existing co-morbidities, particularly allergic disease and asthma, have been found to be significantly associated with increased risk of developing persistent symptoms (Aiyebusi et al., 2021). For children with acute COVID-19, the number of organ symptoms involved independently predicted persisting symptoms and activity impairment (Maddux et al., 2022). In the largest prospective pediatric cohort study of 853 children with the longest follow-up for Long COVID following hospital discharge, older age was associated with persistent symptoms. Children aged 6–12 years had a higher odds ratio for Long COVID (2.57, 95% CI 1.34–5.36) and those aged 12–18 years had an odds ratio of 2.52 (95% CI 1.34–5.01) compared to children 6 years revealed severe acute COVID-19 was associated with persistent symptoms (OR 6.14, 95% CI 1.27–43.94) and excessive weight and obesity with the coexistence of persistent symptoms (OR 2.89, 95% CI 1.12–7.15) (Osmanov et al., 2022). In a multicenter prospective cohort study, clinical impairments following hospitalization for acute COVID or MIS-C were assessed 2–4 months after illness. In MIS-C, pre-existing respiratory conditions, particularly asthma, were associated with ongoing symptoms, and obesity was associated with activity impairment including shortness of breath, fatigue, and/or exercise intolerance (Maddux et al., 2022).

Pathophysiology Fainardi et al. (2022) discussed the possible pathophysiology of Long COVID based on widespread angiotensin converting enzyme-2 (ACE-2) receptor epithelial expression in multiple organs (lungs, heart, brain, oral and nasal mucosa, gastrointestinal tract, pancreas, liver, spleen, kidney, blood vessel endothelium, skin, central nervous system, and peripheral nerves). Chronic tissue damage, persistence of the virus, and immune dysregulation after initial viral infection may lead to autoimmunity and chronic inflammation. Patterns of chronic inflammation may differ between children and adults. Specifically, persistent elevations in interleukin (IL)-6 and IL-1 levels (mediators of inflammation and autoimmunity) which have been demonstrated in adults with Long COVID are not consistently seen in children. During the acute infection, children have been found to have an abnormal distribution of B-cell subsets with higher levels of IgD-CD27+ memory and switched IgMIgD-B cells than controls. The restoration of B-cell homeostasis with higher numbers of naïve unswitched IGM+IgD+ and Igm+CD27-CD38dim B cell subsets is observed with recovery. Naïve and switched IgD-B lymphocytes

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tend to be lower in children with persistent symptoms. Total regulatory T-cells increase in children who completely recover while patients with persistent symptoms do not seem to be able to reconstitute their levels. Patients who fully recover demonstrate an increasing number of peripheral natural T regulatory cells while those with persistent symptoms have reduced levels (Buonseso et al., 2022). In the persistent inflammatory model, after initial damage to the alveolar capillary barrier, chronic inflammation with continuous production of pro-inflammatory cytokines and reactive oxygen species may occur followed by their release into the surrounding tissues and bloodstream. Complement and platelets can be activated, and platelet-leukocyte interactions can lead to further pro-inflammatory cytokine release and impairment of coagulation. Microemboli may form in various organs but especially in the lungs, given the extremely rich expression of ACE-2 receptors in lungs and pulmonary vascular endothelium leading to hypoxemia, tissue hypoxia, and dyspnea. Therefore, prolonged hyperinflammatory responses and hypercoagulability increase the risk for thrombosis which may explain the common respiratory symptoms in patients with Long COVID. The presence of pulmonary circulatory dysfunction with possible microvascular and endothelial damage from chronic inflammation was demonstrated in a case report of a 14-year-old female with mild COVID-19 infection in October 2020, hospitalized for persistent symptoms of tachycardia, chest pain, and easy fatiguability 7 months after acute infection. She had a pro-inflammatory state (elevated IL-6, IL-1, TNKF-a, unusual regulatory T and B cell patterns, low concentrations of CD27+memory B lymphocyte markers) and high levels of IgA and IgG anti-SARS-CoV-2 antibodies. Cardiopulmonary exercise testing suggested mild pulmonary hypertension with minimal overload of the right ventricle and compensatory tachycardia during submaximal effort. Pulmonary scintigraphy was normal, but ventilation-perfusion single photon emission computed tomography (SPECT) revealed a significant diffusion defect in the apical portion of the right upper lobe with no correspondent abnormalities on chest computed tomography (CT) (Buonsenso et al., 2021). Endothelial damage and microthrombosis may also occur in cardiac tissue. Chronic inflammation of cardiac myocytes may lead to myositis and fibrosis. Cardiovascular dysfunction in the afferent autonomic nervous system secondary to infection, autonomic nervous system proinflammatory response, and autoimmunity can lead to postural orthostatic tachycardia syndrome. The rapid resolution of LV dysfunction and coronary artery abnormalities in MISC, unlike the typical course of viral myocarditis or Kawasaki disease, further support the notion that cardiac manifestations are a result of systemic inflammation and vasodilation rather than immune infiltrate mediated damage to the myocardium. Further myocardial edema appears to be the predominant finding on cardiac MRI, not necrosis, fibrosis, or late gadolinium enhancement that is typically seen in cases of classic viral myocarditis. Taken together

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this supports the hypothesis that post-SARS-CoV-2 conditions are a postinfectious hyperinflammatory process (Fainardi et al., 2022; Lopez-Leon et al., 2022). Chronic neuroinflammation could also be the basis of autonomic dysfunction. Long-term inflammation in the CNS could damage neurons, and coagulation abnormalities may lead to thromboembolic events leading to neurologic manifestations such as cognitive impairment. Diffuse tissue damage in the gastrointestinal tract may lead to enterocyte desquamation, edema and small bowel dilation, immune dysregulation with lymphocyte infiltration, microthrombosis, and necrosis. Chronic neuroinflammation and injury may contribute to chronic fatigue along with psychological and social factors (Fainardi et al., 2022).

Symptoms A list of Long COVID symptoms and likelihood at presentation in children is shown in Figure 14.1. Cardiorespiratory symptoms are among the most prominent, particularly shortness of breath/chest tightness, orthostatic intolerance/ dizziness, and chronic fatigue/exercise intolerance. These symptoms will be the focus of this section. In a review of 14 studies reporting on persistent symptoms following COVID a total of 19,426 children and adolescents were identified by Zimmerman et al. (2021). In this meta-analysis there was a large variation in reported frequency of persistent symptoms. Respiratory-related symptoms included congested or runny nose in 1–12%, cough in 1–30%, and chest tightness or pain in 1–31%. Gokcen et al. (2022) reported on 50 children with confirmed COVID-19 with ongoing symptoms 3 months after infection. In 28% of these patients, cough, chest pain and tightness, dyspnea, and exertional dyspnea were reported. Persistent respiratory symptoms were reported in 50% of children with severe disease and in 12.5% with non-severe disease. In a retrospective study by Leftin et al. (2021), 96.6% of patients had persistent dyspnea and/or exertional dyspnea 1 to almost 7 months following an acute infection. Other symptoms included cough, fatigue, and exercise intolerance. The majority of these children with persistent symptoms (62.1%) were obese and a third (37.9%) had prior history of asthma. In a prospective study by Ashkenazi et al. (2021), 60% of patients seen for persistent symptoms had functional impairment 1 to 7 months after acute infection. The most frequent symptoms were fatigue (71%), dyspnea (50%), and myalgia (45.6%); additional symptoms included sleep disturbances (33.3%) and chest pain (31%). Orthostatic intolerance, described in many patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a common finding in adolescents with Long COVID. It refers to a clinical condition in which symptoms of palpitations, lightheadedness/dizziness, syncope, dyspnea, or fatigue are made worse with upright posture (Morrow et al., 2022; Townsend et al., 2020; Rowe et al., 2017). In some instances, post-COVID infection in

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adolescents meets criteria for postural tachycardia syndrome (POTS), which is briefly defined as an excessive heart rate increase (usually greater than 40 beats/minute) without hypotension while upright (Vernino et al., 2021; Morrow et al., 2022). Information on the prevalence and severity of orthostatic intolerance in pediatric patients post-COVID is limited. Meta-analysis suggests a pooled prevalence of around 7% (Lopez-Leon et al., 2022), but is limited by lack of consistency in definitions within the literature and its overlap with other Long COVID symptoms such as fatigue. Case series describing the condition show a significant symptom burden resulting in impaired quality of life and limited ability to participate in school (Drogalis-Kim et al., 2022; Morrow et al., 2021). Orthostatic symptoms and heart rate changes that do not meet the threshold for POTS represent a spectrum of dysautonomia (Morrow et al., 2022). Dysautonomia is a broad term that encompasses multiple disorders of the sympathetic and/or parasympathetic nervous system which, aside from controlling heart rate and blood pressure regulation, controls bodily functions such as breathing, digestion, vision, and mood, and heart rate and blood pressure regulation. Many of the symptoms identified as associated with Long COVID, such as fatigue, sleep disturbance, anxiety, and gastrointestinal symptoms, also overlap with dysautonomia, reinforcing the importance of orthostatic testing in the evaluation of Long COVID symptoms in young patients (Lopez-Leon et al., 2022; Morrow et al., 2022).

Cardiopulmonary Function Testing Fatigue and post-exertional malaise are among the most common symptoms reported in children with Long COVID (Morrow et al., 2021). A recent multicenter prospective study identified persistent symptoms and activity intolerance at 2–4 months after hospitalization for 26.9% of children hospitalized with acute COVID and 30% of those hospitalized with MIS-C (Maddux et al., 2022). Meta-analysis also showed these symptoms were among the most common reported in children who were not hospitalized (Lopez-Leon et al., 2022). There is limited data regarding formal exercise testing in patients who had recent COVID-19 or MIS-C. A 6-minute walk test was assessed in 2 studies, one in a group of 40 children followed after hospitalization for MIS-C (Penner et al., 2021), and the other in a group of 29 children with recent SARS-CoV-2 infection (Leftin et al., 2021). In the MIS-C group, 45% were noted to have 6-minute walk tests below the third percentile for their age and sex at 6 months post-discharge (Penner et al., 2021). In children presenting with respiratory complaints post-SARS-Cov-2 infection, 66% had an abnormal 6-minute walk test defined as Z scores below 1.64 (Leftin et al., 2021). Notably, the patients with impaired 6-minute walk were also noted to have significant tachycardia for age, underscoring the overlap of autonomic dysfunction and orthostatic complaints in these patients.

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Two studies to date have used formal cardiopulmonary exercise testing (CPET) to test symptoms of exercise intolerance in a group of patients after mild SARS-CoV-2 infection or after hospitalization for MIS-C. Both studies showed an abnormal cardiorespiratory response. In the MIS-C group, Astley et al. (2022) showed lower VO2peak, impaired oxidative metabolism (lower VO2VAT and OUES), and ventilatory inefficiency (higher VE/VCO2) compared with normal values for the cohort 1–6 months after hospitalization. In the group with a history of mild SARS-CoV-2 infection but persistent complaints of dyspnea 1–12 months after illness, Ashkenazi-Hoffnung et al. (2021) showed maximal pulse was lower than age-specific mean in all 51 patients who underwent an exercise stress test. In 66% of these patients, the maximal pulse was below the minimal threshold value, further suggesting some degree of chronotropic incompetence and neurovascular dysregulation. While possibly connected to residual cardiac disease, both studies showed that low VO2peak occurred in patients with normal inflammatory markers and normal ventricular systolic function on echocardiogram. Although the above studies show impairments in cardiopulmonary exercise tolerance, none of the studies had a control group for comparison. Interestingly, low VO2peak was found in one retrospective study of healthy children with no known exposure to SARS-CoV-2 when compared to healthy children tested pre-pandemic (Dayton et al., 2021). Another retrospective cohort study of unexposed children who underwent serial CPET pre- and during the pandemic found that predicted peak aerobic capacity significantly decreased during the pandemic, even after adjusting for changes in somatic growth (Burstein et al., 2022). It is unclear if the persistent symptoms of Long COVID are from deconditioning as suggested by these healthy control studies or from pathobiology related to the illness itself. Patients with respiratory symptoms should undergo pulmonary function testing (PFTs) when able to do so, acknowledging that there are factors that may preclude testing such as developmental constraints, age, and persistent respiratory symptoms such as cough. A limitation of studies involving lung function testing is the lack of baseline pre-COVID infection evaluation of patients. While long-lasting deterioration of pulmonary function has been described in adults, there are few reports on the extent of changes in pulmonary function in children, and these have not identified clear residual testing abnormalities. Abnormalities in PFTs after SARS-CoV-2 infection are rare. In a study of a small number of children with history of mild SARS-CoV-2 infection, most demonstrated normal pulmonary function testing and diffusion capacity two months after recovery (Knoke et al., 2022). Further, the proportion of children and adolescents with impaired pulmonary function (mainly abnormal LCI2.5, reduced FVC, and impaired DLCO) after SARS-CoV-2 infection was not significantly higher than controls. Another cohort of children with protracted respiratory symptoms >6 weeks after SARS-CoV-2 infection was found to have primarily normal results on spirometry, plethysmography, and diffusion capacity testing (Leftin et al., 2021). Finally, a single-center study comparing

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pulmonary function testing in 73 children and adolescents after SARS-CoV-2 seroconversion demonstrated lack of impairment except in those with severe infection; in addition, there was no difference in follow-up pulmonary function testing compared with a group of healthy controls (Vernino et al., 2021). The mechanisms underlying the discrepancy between subjective persistent respiratory complaints and normal pulmonary function in children with Long COVID are unclear, but this finding has similarity to what has been reported in ME/CFS. Although rare, there are studies that report significant PFT abnormalities. In the case series by Gokcen et al. (2022), diffusing capacity for carbon monoxide (DLCO) was significantly lower in the severe disease group. Moreover, significant decreases in FEV1/FVC and an increase in lung clearance index were found in patients with persistent respiratory symptoms. In the study by Ashkenazi et al. (2021), 45% of patients who underwent PFTs had abnormal findings consisting of mild obstructive defect on spirometry and air trapping based on plethysmography. More than half showed reversibility of obstructive defect after bronchodilator, underscoring the importance of PFT in informing treatment options.

Clinical Applications/Management and Treatment As we continue to learn about the pathophysiology of Long COVID in children and adolescents, providers should continue taking a cautious approach to the management of this patient population. In addition to obtaining a careful history of SARS-CoV-2 illness, complications, and comorbidities, testing in children and adolescents with Long COVID (severe illness as well as mild) should include laboratory analysis, echocardiogram +/– cardiac MRI, spirometry with bronchodilator administration, plethysmography and diffusion capacity testing, cardiopulmonary exercise testing, and orthostatic testing. Recommendations for testing after SARS-CoV-2-associated myocarditis and vaccine-associated myocarditis are outside the scope of this chapter. An overview of diagnosis and management is summarized in Figure 14.2. This highlights the importance of multidisciplinary care since many subspecialties may be involved in the management of these patients. Testing should be guided by findings from history and physical examination as well as results of previous diagnostic testing. The following discussion will describe the various testing and management approaches from our own institution as well as from different centers and working groups. In our institution, children with MIS-C are followed by cardiology, infectious disease, and their pediatricians upon discharge. Infectious disease followup is within 2 weeks of discharge, and pediatrician follow-up is within 4 weeks of discharge. In cardiology patients are clinically followed with EKGs and echocardiography at approximately 2 weeks, 8 weeks, 6 months, and 1 year post-admission. Some patients are seen more frequently as clinically indicated. Inflammatory markers and cardiac biomarkers (e.g., troponins, plasma brain

Proposed Management Strategies:

Laboratory: • CBC with differential • Comprehensive Metabolic Panel • ESR/CRP • Thyroid Function • Ferritin & other measures of iron deficiency • Vitamin B12, vitamin D • Celiac disease screening • Creatine phosphokinase • ANA (anti-nuclear antibodies) • Histamine (if allergic history to r/o mast cell activation syndrome) • Other tests based on symptoms/physical findings

Referrals: • Cardiology • Pulmonology • Infections Disease • Neurology • Gastroenterology • Allergy/Immunology • Rheumatology • Rehabilitation Medicine • Psychology

Post COVID-19 Complications and Sequelae: • Pulmonary Fibrosis • Pulmonary Embolism • Post-ICU Syndrome • Critical Illness Myopathy • Residual cardiac dysfunction • Post-Covid Auto-Inflammatory Syndrome (MIS-C) • Deconditioning

Previous Conditions: • Asthma flare New Conditions: • Hypothyroid • Celiac Disease/IBD • Lupus • Lyme/EBV

Differential Diagnosis

Figure 14.2 The clinical evaluation, diagnostic assessment, testing, and treatment considerations for pediatric Long COVID.

Respiratory symptoms: Consider bronchodilators, steroids, pulmonary rehabilitation Cardiovascular dysfunction: Consider ACE/ARB if ventricular dysfunction, anti-arrhythmic drugs if abnormal Holter Allergies/Inflammation: Consider anti-histamine, NSAIDS, steroids Orthostatic/POTS: Increase salt, water intake, consider medications (fludrocortisone, B-blockers) and rehab program

• 6-minute walk, 1-minute sit-tostand test • CXR, CT scan chest or CT Angiogram

diffusion capacity testing

• Spirometry/plethysmography/

• Orthostatic Testing

• Cardiopulmonary exercise testing

Testing: • Echocardiography/EKG

History: • Mood changes/sleep disorders • Decreased cognition/headache • Fatigue & post-exertional malaise • Shortness of breath/exercise intolerance • Cough/chest pain/chest tightness • Orthostatic intolerance • Abdominal pain, constipation Questionnaires: • AHA 14-Element Screening • Pediatric Quality of Life • ISARIC pediatric questionnaire Physical Exam: • Neurologic Exam • Orthostatic Maneuvers

Pediatrician Visit 4-12 weeks after Acute COVID Infection

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natriuretic peptide (pro-BNP), and plasma C-reactive protein (CRP)) are trended until normalized. We perform a Holter, cardiopulmonary stress test, and cardiac MRI for those with left ventricular dysfunction and significantly elevated troponins (e.g., MIS-C associated myocarditis). For those with normal ventricular function on echocardiogram but persistent shortness of breath or exercise intolerance at 3 months post-discharge, we refer to pulmonology for PFTs, imaging, and bronchodilator therapy as clinically indicated. Other referrals and testing are made based on symptom persistence as referenced in Figure 14.2. For children with acute COVID/SARS-CoV-2 infection, we recommend an initial pediatrician visit around 4 weeks from illness with history and physical assessing for Long COVID symptoms as suggested in Figure 14.2. Special emphasis is placed on the AHA 14-Element screen and cardiac symptoms of chest pain, shortness of breath, exercise intolerance, new-onset palpitations, or syncope. If this is abnormal, referral to cardiology is recommend where EKG and echocardiogram are performed. Orthostatic testing, Holter, and cardiopulmonary stress tests are cardiac biomarkers performed as clinically indicated. For shortness of breath and cough out of proportion to expected recovery from infection, pulmonology referral is recommended with associated PFTs, imaging, and bronchodilator therapy as clinically indicated. For those with allergic history, an allergy and immunology referral is recommended to assess for associated mast cell activation syndrome and benefit of antihistamines. For symptoms of headache, school disturbance/concentration difficulties, and sleep disturbance, a referral to neurology is made. Basic screening labs such as CBC, complete metabolic panel, and inflammatory markers such as CRP can be performed at the 4-week visit. Repeat visit at 8–12 weeks with further testing and referral based on symptoms persistence as referenced in Figure 14.2. Although not routine for our practice, the following tests have been described for respiratory, cardiovascular, and neurologic symptoms. In patients who complain of exertional dyspnea, exercise capacity tests such as a 1-minute sit-to-stand test, 2-minute step test, 10-meter walk test, and the 6-minute walk test have been done. Patients with fatigue or neurological issues may require EEG and polysomnography. Further levels of testing for persistent symptoms or abnormal tests have included brain and/or cardiac MRI, CT angiogram, and lung SPECT scans. The goal of medical management is to optimize function and quality of life. Management is optimal if approached from a multidisciplinary perspective as patients invariably present with several symptoms that are not limited to one organ system. A physical rehabilitation plan might be conducted cautiously for patients with exercise intolerance who have ME/CFS. The National Institute for Health and CARE Excellence (NICE), the Royal College of General Practitioners (RCGP), and the Scottish Intercollegiate Guidelines Network (SIGN) published guidelines for adults, children, and adolescents on the assessment and management of the long-term effects of COVID-19 for health care practitioners (NICE, guideline 2020). They

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recommended tailoring tests and investigations to signs and symptoms to rule out acute or life-threatening complications, and to determine if symptoms are likely caused by ongoing symptomatic COVID-19, post-COVID-19 syndrome, or could be a new, unrelated diagnosis. Blood tests including a CBC, kidney and liver function, C-reactive proteins, ferritin, B-type natriuretic peptide, and thyroid function tests may be sent. If appropriate, an exercise test such as a 1-minute sit-to-stand test may be assessed with recording of breathlessness, heart rate, and oxygen saturation. Patients with ongoing respiratory symptoms at 12 weeks may be offered a chest X-ray. Once acute or lifethreatening complications or alternative diagnosis are ruled out, patients may be referred to an integrated multidisciplinary service any time from 4 weeks after the acute COVID infection. A comprehensive multidisciplinary assessment should lead to shared decision-making with regards to the need for support and rehabilitation. Physical, psychological, and psychiatric aspects of rehabilitation should be considered and assessed. Based on clinical need and local resources, this may include advice on self-management, support for integrated primary care, community, rehabilitation and mental health services, referral to an integrated multidisciplinary service, or referral to specialist care for specific complications. Referral for specialist advice should be considered in children with ongoing symptomatic COVID-19 or post-COVID-19 syndrome. The Catalan Society of Family and Community Medicine established a working group, made up of 90% primary care professionals, along with specialists in internal medicine, autoimmune diseases, infectious disease, epidemiology, and statistics, to develop clinical practice guidelines for patients with Long COVID not requiring hospitalization focused primarily on primary care evaluations and outpatient support (Siso-Almiral et al., 2021). They recommended that care of Long COVID patients be structured in three consecutive visits (4 weeks, 8 weeks, and 12 weeks) according to the time from diagnosis of acute COVID 19-infection with a positive PCR, antigen, or antibody test or after the start of signs and symptoms of acute COVID where laboratory testing is unavailable. The first primary care visit should focus on the patient’s past medical history, symptoms, characteristics of COVID-19 infection, physical examination, and laboratory tests. The family physician or primary care specialist should have the most comprehensive long-term information on pre-infection status, including underlying medical conditions or co-morbidities. Information on the acute infection, i.e., symptoms and approximate date of onset, hospital admission, discharge dates, maximum oxygen requirements, ICU admission and duration, therapies received, and complications during admission, should be recorded. A visual analog scale (0–10) may be used to subjectively assess the intensity of symptoms. A complete physical examination paying special attention to assessing the oropharynx and cardiorespiratory system, vital signs, and oxygen saturation should be done. Basic laboratory studies should depend upon symptoms: for example, a CBC, CRP, D-dimer, comprehensive metabolic panel may be

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sent on all patients, whereas muscular enzymes could also be sent on patients with myalgia, chest pain, and/or dyspnea. Anti-transglutaminase antibodies may be measured in patients with gastrointestinal complaints. EKGs, CXRs, and spirometry may be sent on patients with myalgia, chest pain, cough, and/ or dyspnea. At a visit around 8 weeks, results of testing can be discussed and differential diagnosis with other post-COVID conditions should be ruled out. The Catalan group formulated symptom-specific algorithms to identify potential causes to explain and workup various patient symptoms. A third primary care visit completed at around 12 weeks post-acute infection is intended to evaluate for long-term symptoms and re-evaluate possible causes. This is the time when the Catalan group recommends that patients with persistent symptoms be referred to specialists for further workup and management. The profound, prolonged fatigue after COVID-19 shares characteristics with ME/CFS and has been described after other infections including SARS, MERS, and community-acquired pneumonia. No association has been found between long-term fatigue associated with COVID-19 severity and laboratory markers of inflammation. Women and patients with a pre-existing diagnosis of depression and anxiety were over-represented in patients with long-term fatigue. In patients with fatigue >4 weeks after acute COVID-19, specific history during the first primary care visit should focus on onset date, symptoms and accompanying signs, concomitant psychosocial and emotional factors, related drugs, sleep disorders, and exposure to toxins. Laboratory tests may include serum chloride, bicarbonate, phosphate, muscle enzymes, plasma cortisol levels, and spirometry. The diagnostic approach to patients with cough persisting >4 weeks after acute COVID-19 infection should include the date and characteristics (dry, irritating, non-productive, or productive of sputum). Possible sequelae from severe COVID-19 infection that may result in coughing or iatrogenic sequelae related to invasive maneuvers such as intubation or tracheostomy should be evaluated. Spirometry, if safe, is advised. Long-term dyspnea has been reported in 11–33% of patients at 4 weeks and 8–63% of patients at 8 weeks postCOVID. Specific history in these patients should include onset and characteristics of the symptoms. Primary care providers also need to be aware of the impact of isolation on decreased physical activity and exacerbation or worsening of mental health issues such as anxiety and depression. The International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterization Protocol allows recruitment of patients globally who can be studied prospectively during ongoing pandemics. A report of a large cohort of 853 children from Russia utilized the ISARIC COVID-19 Health and Wellbeing Follow-up Survey for children to assess patients’ physical and psychosocial wellbeing and behavior following hospitalization for COVID-19. The study reported on risk factors and duration of persistent symptoms following COVID-19 infection. The ISARIC

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initiative allows different countries to harmonize and compare COVID-19 reports on a global scale (Osmanov et al., 2022). The Italian intersociety consensus on management of Long COVID in children recommends that primary care physicians evaluate children after 4 weeks from COVID-19 diagnosis (Esposito et al., 2022). They developed a pediatric questionnaire containing common symptoms of pediatric Long COVID to obtain detailed information on the development of the syndrome. Subsequent follow-up at 3 months after the acute infection should be done to confirm normality or to address emerging problems. Further evaluation depends upon the characteristics of their clinical manifestations. Referrals may need to be made to customized programs based on clinical symptoms. If children develop significant mental problems after 12 weeks, psychological intervention with continuous psychological support is mandatory. Following an initial evaluation at 4–12 weeks to screen for symptoms and perform a physical examination, children who continue to have symptoms suggestive of Long COVID after 12 weeks from onset of acute illness may enter a secondary phase of investigations based on their symptoms. Lung function testing may include spirometry, impulse oscillometry, lung clearance index, or exhaled nitric oxide. Further investigations should be tailored based on symptoms including a CBC, C-reactive protein, hepatorenal function, blood coagulation, and urine tests. Radiologic tests may include a CXR, ultrasound, or chest CT scan. Cardiology exam may include EKG and echocardiogram. Sleep disturbances may be worked up with nocturnal oximetry or polysomnogram. Psychological, gastroenterological, and dermatologic evaluations may be needed based on symptoms. Follow-up with pulmonary function testing may be done at 3-, 6-, and 12-month intervals based on patient impairment. Rehabilitation has also been suggested for patients with functional limitations. Some patients may require medical treatment such as bronchodilators and inhaled steroids (Fainardi et al., 2022). Multidisciplinary clinics are now emerging in tertiary care centers to address the multitude of persistent symptoms in children with Long COVID. Ashkenazi-Hoffnung et al. (2021) published a preliminary prospective study from a designated multidisciplinary post-COVID clinic in a tertiary care center. Ninety children, 12+5 years of age, presented at a median of 112 days post-acute COVID -19 infection. Despite mild acute disease and a lack of previous illness, 60% of symptoms were associated with functional impairment on PFTs 1–7 months post-infection. Twenty-seven (45.0%) of the 60 patients who underwent pulmonary function testing due to cardiopulmonary symptoms had primarily a mild obstructive pattern with more than half exhibiting reversibility with bronchodilators. Their study supports the potential for treatment with bronchodilators and inhaled corticosteroids. Since long-term sequelae following COVID-19 include fatigue, breathlessness, and functional limitations, pulmonary rehabilitation has been recommended for both adults and children. A prospective observational 6-week study in adults by Nopp et al. (2022) demonstrated significant improvements

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in their 6-minute walk distance at 4 months post-infection from 584.1 m to 647.0 m, a lowering of one grade on post-COVID-19 functional status scale, as well as significant improvement across secondary endpoints (i.e., dyspnea, fatigue, and quality of life). Pulmonary function parameters FEV1, DLCO, and measurements of inspiratory muscle strength also improved significantly. Data on the benefits of rehabilitation in children are limited. Morrow et al. (2021) published a case series in 2021 from the post-COVID-19 Rehabilitation Clinic at the Kennedy Krieger Institute in Baltimore, Maryland. The initial cohort of 9 patients