A Long COVID Definition: A Chronic, Systemic Disease State with Profound Consequences (2024)

Consensus Study Report

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This activity was supported by a contract between the National Academy of Sciences and the Administration for Strategic Preparedness and Response (75A50121C00061). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-71908-7
International Standard Book Number-10: 0-309-71908-9
Digital Object Identifier: https://doi.org/10.17226/27768

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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. A Long COVID definition: A chronic, systemic disease state with profound consequences. Washington, DC: The National Academies Press. https://doi.org/10.17226/27768.

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COMMITTEE ON EXAMINING THE WORKING DEFINITION FOR LONG COVID

HARVEY V. FINEBERG (Chair), President, Gordon and Betty Moore Foundation

KEVIN M. ALEXANDER, Assistant Professor of Medicine, Stanford University

DONALD BERWICK, President Emeritus and Senior Fellow, Institute for Healthcare Improvement

KARYN BISHOF, President and Founder, COVID-19 Longhauler Advocacy Project (C19LAP), Long COVID Patient Advocate

LILY CHU, Vice President, International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

BETTY DIAMOND, Director of the Institute of Molecular Medicine, Head/Professor, The Center for Autoimmune, Musculoskeletal, and Hematopoietic Diseases, Feinstein Institutes for Medical Research, Northwell Health

ABIGAIL DUMES, Assistant Professor, Department of Women’s and Gender Studies, University of Michigan

E. WESLEY ELY, Grant W. Liddle Chair in Medicine, Professor of Medicine, Co-Director, Critical Illness, Brain Dysfunction, and Survivorship Center, Associate Director of Aging Research, Vanderbilt University Medical Center

DENNIS LARRY KOLSON, Professor of Neurology, Department of Neurology, Perelman School of Medicine, University of Pennsylvania

JERRY KRISHNAN, Professor of Medicine and Public Health, Associate Vice Chancellor for Population Health Sciences, Office of the Vice Chancellor for Health Affairs, University of Ilinois Chicago

PETER PALESE, Horace W. Goldsmith Professor, Department of Microbiology, Professor Department of Medicine, Icahn School of Medicine at Mount Sinai

CAITLIN PEDATI, Public Health District Director, Virginia Beach Department of Public Health

LINDA SPRAGUE MARTINEZ, Professor, Departments of Medicine and Public Health Sciences, Director, Health Disparities Institute (HDI), UConn Health

MARK SMOLINSKI, President, Ending Pandemics

ANDREA B. TROXEL, Director of the Division of Biostatistics, Professor of Population Health, New York University Grossman School of Medicine

MONICA VERDUZCO-GUTIERREZ, Professor and Distinguished Chair, Department of Rehabilitation Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, Clinical Chief of Physical Medicine and Rehabilitation at the University Health System, Medical Director of Critical Illness Recovery and Neurorehabilitation at Warm Springs Rehabilitation Hospital in San Antonio

National Academy of Medicine Fellows

PAULE JOSEPH, National Institutes of Health Lasker Scholar and Distinguished Scholar, Chief of the Section of Sensory Science and Metabolism in the Division of Intramural Clinical and Biological Research at the National Institute on Alcohol Abuse and Alcoholism with a dual appointment at the National Institute of Nursing Research

BEN WESTON, Associate Professor in the Department of Emergency Medicine at the Medical College of Wisconsin

Study Staff

LISA BROWN, Study Director

TEQUAM WORKU, Program Officer

SHALINI SINGARVELU, Program Officer

MATTHEW MASIELLO, Associate Program Officer

MARGARET MCCARTHY, Research Associate (until December 31, 2023)

BURGESS MANOBAH, Research Associate (from January 1, 2024)

RAYANE SILVA-CURRAN, Senior Program Assistant

JULIE PAVLIN, Senior Board Director, Board on Global Health

CLARE STROUD, Senior Board Director, Board on Health Sciences Policy

Consultant and Intern

ILANA GOLDOWITZ, Science Writer, Striga Scientific, LLC

JACQUELINE BRENNER, Intern, M.D./M.P.H. candidate at the University of Miami Miller School of Medicine

Reviewers

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following individuals for their review of this report:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of this report was overseen by ENRIQUETA C. BOND, Burroughs Wellcome Fund, and SUSAN J. CURRY, The University of Iowa. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

Contents

ACRONYMS AND ABBREVIATIONS

PREFACE

SUMMARY

1 INTRODUCTION

Prevalence of Long COVID Globally and in the United States

Need for a Clear Definition

Charge to the Committee

Study Approach

2024 NASEM LONG COVID DEFINITION

2 DEFINING LONG COVID

A Definition Designed to Evolve as New Evidence and Understanding Emerge

Evidence Supporting Key Elements of the Definition

Considerations for Implementation and Different Uses

A Working Definition and Research Agenda

Shortcomings in the Available Evidence

Limitation and Unintended Consequences of the Definition

Concluding Remarks and Recommendations

References

APPENDIXES

A DETAILED DESCRIPTION OF COMMITTEE’S APPROACH AND STUDY METHODS

B MEASURES OF DIAGNOSTIC PERFORMANCE: SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUE

C BIOGRAPHICAL SKETCHES

Boxes, Figures, and Tables

BOXES

S-1 2024 NASEM Long COVID Definition

1 Selected Existing Long COVID Definitions and Descriptions

2 Statement of Task

FIGURES

S-1 Definition figure: 2024 NASEM Long COVID definition

1 Process map for the multi-phase activity of examining the working definition for Long COVID

2 National Long COVID programs and initiatives

3 Definition figure: 2024 NASEM Long COVID definition

4 Frequencies of new onset symptoms

5 Hypothesized mechanisms of Long COVID pathogenesis

TABLES

1 Possible Key Elements of a Disease Definition

2 2024 NASEM Long COVID Definition Implementation Checklist for Clinicians

3 Study Design Considerations for Application of the 2024 NASEM Long COVID Definition

4 Public Health Surveillance Approaches for Long COVID

Acronyms and Abbreviations

Acknowledgments

This Consensus Study Report would not have been possible without the many experts—especially those with Long COVID—who generously contributed their time and expertise to inform the development of this report. The committee sincerely thanks EnSpark Consulting who led the engagement efforts and all those who participated in these efforts, as well as the speakers listed in Appendix A for their timely participation and expert contributions to the public workshops.

The committee would also like to thank the sponsor of this study, the Administration for Strategic Preparedness and Response (ASPR) and the Office of Assistant Secretary for Health (OASH). The committee also extends their gratitude to the group of interagency federal experts, including those at the National Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC), for informing the committee’s charge.

Many others within the National Academies supported this project. The committee thanks the staff of the Health and Medicine Division (HMD) Executive Office, Office of Communications, Office of Governmental Affairs, and Research Center. The committee is grateful to Ilana Goldowitz for her invaluable contributions to report writing. Finally, Robert Pool is to be credited for his editorial assistance in preparing this report.

Lastly, we are deeply grateful to the members of the Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats who planned and conducted three scoping and information-gathering meetings that helped to inform and shape this effort.

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Preface

Defining a widespread, poorly understood medical condition, such as Long COVID, is a freighted task. Patient groups, clinicians and researchers, government agencies, and international organizations have used different terms to name the condition and diverse descriptions to determine what fits the term. No well-documented, pathophysiological cascade nor any sufficiently discriminating biomarker can today definitively diagnose Long COVID. While most people infected with SARS-CoV-2 fully recover, tens of millions worldwide experience persistent symptoms and organ damage as well as other consequences for months to years after acute infection. As a result, patients can remain unacknowledged, in a kind of diagnostic limbo.

Inconsistent disease terminology and meaning can confound clinicians; limit the generalizability of research findings; and inhibit patients from obtaining the recognition, care, and support they need. Concerns about the adequacy and acceptability of existing definitions of Long COVID led units within the U.S. Department of Health and Human Services to ask the National Academies of Sciences, Engineering, and Medicine (the National Academies) to put forth a new definition for Long COVID. This report conveys the National Academies’ response: the 2024 NASEM Long COVID Definition.

The approach and conclusions of the committee that prepared this report differ from the usual process and product of the National Academies in a couple ways. First, most committees rely mainly on a range of technical experts to craft a report, sometimes obtaining input from others. This

committee adopted a systematic and multi-phase information-gathering process that relied strongly on the insights of patients and other members of the public in addition to extensive literature and knowledge across a range of disciplines. The committee benefited from having some individual members who, whatever else their qualifications, brought personal experience with Long COVID and other infection-associated chronic conditions (IACCs). The report and an appendix explain in detail the array of evidence and input used by the committee.

Second, most committees of the National Academies aim for their conclusions to be the final word on a topic. By contrast, this committee anticipates, indeed recommends, that its definition be reviewed and revised in light of emerging knowledge and deeper understanding of Long COVID, including pathways of pathobiology and possible recognition of reliable and accurate biomarkers. Words have a way of evolving from their original meaning: nice originally meant silly or foolish, and silly originally referred to things worthy or blessed. While Long COVID is unlikely to endure such an extreme lexical conversion, its meaning can and should evolve to match the state of knowledge.

On behalf of the committee and the project staff, I extend my sincere thanks to the many individuals who shared their time and expertise to support the committee’s work and inform its deliberations. The study was sponsored by the Administration for Strategic Preparedness and Response and the Office of the Assistant Secretary for Health, and we thank Rear Admiral Michael Iademarco, Allison O’Donnell, and Margaret Sloane for their guidance and support. We also thank the many experts who freely contributed their views. The committee especially appreciates the perspectives provided by people living with Long COVID who took the time and made the effort to contribute to our deliberations. This project began under the aegis of the National Academies Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats, and we owe every member of the standing committee a debt for helping to shape the earliest stages of this work.

It has been a privilege and joy to work with the Academies staff who so ably supported this project. Special recognition goes to Lisa Brown, staff director, and to Tequam Worku, Shalini Singaravelu, Matthew Masiello, Rayane Silva-Curran, Margaret McCarthy, and Burgess Manobah, along with National Academy of Medicine fellows Paule Joseph and Ben Watson and intern Jackie Brenner. Ilana Goldowitz provided research and writing assistance. The committee extends our gratitude also to Clare Stroud, senior board director of the Board on Health Sciences Policy.

Finally, I would like to thank my fellow committee members who so generously volunteered to take up this task. The committee’s steadfast

engagement, active and energetic exchange of ideas, and cooperative spirit made preparing this report not only possible, but a highly rewarding experience. We hope it proves useful and is also a source of gratification to the many patients, family members, clinicians, researchers, officials, and others who contributed.

Harvey V. Fineberg, Chair
Committee on Examining the Working Definition for Long COVID
Standing Committee on Emerging Infectious Diseases and 21st Century Health Threats

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