NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

National Academy of Sciences and the American Society of Tropical Medicine and Hygiene; Burroughs Wellcome Fund (Contract No. 1022390); EcoHealth Alliance; Infectious Diseases Society of America; Johnson & Johnson (Contract No. C2022024120); Merck and Co. (Grant No. MEM-22-160471); National Center of Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (Contract No. 75D30121D11240, Order No. 75D30122F00011); National Institute of Allergy and Infectious Diseases, National Institutes of Health (Contract No. HHSN263201800029I, Task Order No. HHSN26300011); New Venture Fund (Grant No. NVF-NGDF-NAT10-Subgrant-022263-2023-08-01); Rockefeller Foundation; Sanofi Pasteur; the Society of Infectious Diseases Pharmacists; Steven & Alexandra Cohen Foundation (Award No. Lyme 76); Uniformed Services University of Health Sciences (Award No. HU00012210001); U.S. Agency for International Development (Grant No. 7200AA18GR00003); U.S. Department of Veterans Affairs (Contract No. 36C25022Q1147); and U.S. Food and Drug Administration (Award No. 5R13FD006897-03). 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: 978-0-309-71524-9
International Standard Book Number-10: 0-309-71524-5
Digital Object Identifier: https://doi.org/10.17226/27462

This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu.

Copyright 2024 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved.

Printed in the United States of America.

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Toward a common research agenda in infection-associated chronic illnesses: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/27462.

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president.

The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president.

The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president.

The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine.

Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task.

Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies.

Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release.

For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

TOWARD A COMMON RESEARCH AGENDA IN INFECTION-ASSOCIATED CHRONIC ILLNESSES: A WORKSHOP TO EXAMINE COMMON, OVERLAPPING CLINICAL AND BIOLOGICAL FACTORS WORKSHOP PLANNING COMMITTEE¹

TIMOTHY COETZEE (Cochair), Chief Advocacy, Services and Science Officer, National Multiple Sclerosis Society

TIMOTHY ENDY (Cochair), Program Leader, Coalition for Epidemic Preparedness Innovations

BRIAN FALLON, Director, Lyme and Tick-Borne Diseases Research Center, Clinical Trials Network for Lyme and Tick-Borne Diseases, Center for Neuroinflammatory and Somatic Disorders, Columbia University Irving Medical Center; Professor, New York State Psychiatric Institute

LORRAINE JOHNSON, Chief Executive Officer and Director, LymeDisease.org; Principal Investigator, MyLymeData

AVINDRA NATH, Senior Investigator and Clinical Director, National Institute of Neurological Disorders and Stroke

MELISSA NOLAN, Assistant Professor, Arnold School of Public Health, University of South Carolina; Research Fellow, Prisma Health; Research Fellow, South Carolina Department of Health and Environmental Control

RAFAEL OBREGÓN, Country Representative, UNICEF Paraguay

AMY PROAL, President, PolyBio Research Foundation

PETER ROWE, Professor of Pediatrics, Sunshine Natural Wellbeing Professor of Chronic Fatigue and Related Disorders, Johns Hopkins University School of Medicine

National Academies Staff

ELIZABETH ASHBY, Program Officer

CLAIRE BIFFL, Research Associate

NICKY KUANG, Senior Program Assistant (until October 2023)

JULIE LIAO, Director, Forum on Microbial Threats

JULIE PAVLIN, Senior Board Director, Board on Global Health

SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders

EVA CHILDERS, Associate Program Officer

MAYA THIRKILL, Associate Program Officer

EDEN NELEMAN, Senior Program Assistant (until August 2023)

KIMBERLY OGUN, Senior Program Assistant

CLARE STROUD, Senior Director, Board on Health Sciences Policy

FORUM ON MICROBIAL THREATS

PETER DASZAK (Chair), President, EcoHealth Alliance

CRISTINA CASSETTI (Vice Chair), Deputy Director, Division of Microbial and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health

KENT E. KESTER (Vice Chair), Vice President of Translational Medicine, International AIDS Vaccine Initiative

EMILY ABRAHAM, Director, External Affairs and Policy, Global Public Health at Johnson & Johnson

KEVIN ANDERSON, retired, formerly U.S. Department of Homeland Security

DAN BAROUCH, Director, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center; William Bosworth Castle Professor of Medicine, Harvard Medical School

DANIEL BAUSCH, President, American Society of Tropical Medicine and Hygiene; Senior Director, Emerging Threats & Global Health Security, FIND

NAHID BHADELIA, Founding Director, Boston University Center for Emerging Infectious Disease Policy and Research

CHRISTOPHER BRADEN, Deputy Director, National Center for Emerging Zoonotic & Infectious Diseases, U.S. Centers for Disease Control and Prevention

RICK A. BRIGHT, Founder, Bright Global Health

AMBIKA BUMB, Deputy Executive Director, Bipartisan Commission on Biodefense

ANDREW CLEMENTS, Senior Scientific Advisor, Emerging Threats Division, U.S. Agency for International Development

MALICK DIARA, Public Health Manager, Corporate Medicine and Occupational Health Department, ExxonMobil

SCOTT F. DOWELL, Deputy Director for Surveillance and Epidemiology, Bill & Melinda Gates Foundation

GREG FRANK, Director of Global Public Policy, Merck & Co., Inc.

WONDWOSSEN GEBREYES, Executive Director of Global One Health Initiative, Department of Veterinary Preventive Medicine, The Ohio State University

BRUCE GELLIN, Senior Vice President and Chief of Global Public Health Strategy, Rockefeller Foundation

GIGI KWIK GRONVALL, Senior Scholar, Johns Hopkins University Center for Health Security

JON H. HEINRICHS, Associate Vice President and R&D New Targets, Franchise Head in Portfolio Strategy and Execution, Sanofi Vaccines

ELIZABETH D. HERMSEN, Lead, Global Antimicrobial Resistance & Antimicrobial Stewardship Medical Affairs, Pfizer

ALBERT I. KO, Raj and Indra Nooyi Professor of Public Health, Yale School of Public Health; Professor of Epidemiology and Medicine, Yale School of Medicine

MARK G. KORTEPETER, Vice President for Research, Professor of Preventive Medicine and Medicine, Uniformed Services University of the Health Sciences

LINDA S. LLOYD, Independent Consultant; Adjunct Faculty, San Diego State University School of Public Health

SYRA MADAD, System-wide Special Pathogens Program at NYC Health + Hospitals

JONNA A. K. MAZET, Vice Provost—Grand Challenges, Chancellor’s Leadership Distinguished Professor of Epidemiology and Disease Ecology, University of California, Davis

VICTORIA McGOVERN, Senior Program Officer, Burroughs Wellcome Fund

SUMIKO MEKARU, Vice President, Research & Innovation, The Public Health Company

TIMOTHY D. MURRAY, Professor, Rosalie and Harold Rea Brown Distinguished Endowed Chair, Washington State University

MELISSA NOLAN, Assistant Professor, Arnold School of Public Health, University of South Carolina

RAFAEL OBREGÓN, Country Representative, UNICEF Paraguay

BENJAMIN PINSKY, Professor of Pathology and Medicine, Stanford University School of Medicine

AMEET J. PINTO, Associate Professor and Carlton S. Wilder Junior Faculty Chair, Georgia Institute of Technology

P. DAVID ROGERS, Chair, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital

GARY A. ROSELLE, Executive Director, National Infectious Disease Services Program, Veterans Health Administration, U.S. Department of Veterans Affairs

UMAIR SHAH, Secretary of Health, Washington State

JONATHAN SLEEMAN, Center Director, U.S. Geological Survey Wildlife Health Center

MATTHEW ZAHN, Deputy Health Officer, Orange County Health Care Agency

Forum on Microbial Threats Staff

ELIZABETH ASHBY, Program Officer

CLAIRE BIFFL, Research Associate

NICKY KUANG, Senior Program Assistant (until October 2023)

JULIE LIAO, Director, Forum on Microbial Threats

JULIE PAVLIN, Senior Board Director, Board on Global Health

FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS

FRANCES JENSEN (Co-Chair), Professor and Chair, Department of Neurology, University of Pennsylvania

JOHN KRYSTAL (Co-Chair), Chief of Psychiatry and Behavioral Health, Yale University

RITA BALICE-GORDON, Chief Executive Officer, Muna Therapeutics

DEANNA BARCH, Professor and Vice Dean of Research in Arts & Sciences, Washington University in St. Louis

DIANE BOVENKAMP, Vice President, Scientific Affairs, BrightFocus Foundation

KATJA BROSE, Science Program Officer, The Chan Zuckerberg Initiative

TERESA BURACCHIO, Director, Division of Neurology, Acting Director, Office of Neuroscience, Food and Drug Administration

SARAH CADDICK, Senior Advisor, The Gatsby Charitable Foundation

ROSA CANET-AVILÉS, Vice President, Scientific Programs, California Institute for Regenerative Medicine

MARIA CARRILO, Chief Science Officer, Medical Scientific Relations, Alzheimer’s Association

MICHAEL CHIANG, Director, National Eye Institute

TIMOTHY COETZEE, Chief Advocacy, Services, and Research Officer, National Multiple Sclerosis Society

BEVERLY DAVIDSON, Director, Raymond G. Perelman Center for Cellular and Molecular Therapeutics; Arthur V. Meigs Chair in Pediatrics, The Children’s Hospital of Philadelphia; Professor of Pathology and Laboratory Medicine, University of Pennsylvania

NITA FARAHANY, Professor of Law, Professor of Philosophy, Duke University

EVA FELDMAN, Russell N. DeJong Professor of Neurology; Director, NeuroNetwork for Emerging Therapies and ALS Center of Excellence, University of Michigan

BRIAN FISKE, The Michael J. Fox Foundation for Parkinson’s Research

JOSHUA GORDON, Director, National Institute of Mental Health

MORTEN GRUNNET, Director, Research & Development, Lundbeck

MAGALI HAAS, Founder and Chief Executive Officer, Cohen Veterans Bioscience

RICHARD HODES, Director, National Institute on Aging

STUART HOFFMAN, Senior Health Science Officer for Traumatic Brain Injury, Department of Veterans Affairs

YASMIN HURD, Director, Addiction Institute, Icahn School of Medicine at Mount Sinai

STEVEN HYMAN, Director, Stanley Center for Psychiatric Research, Distinguished Service Professor, Professor of Stem Cell Biology and Regenerative Biology, The Broad Institute of MIT and Harvard

MICHAEL IRIZARRY, Vice-President, Clinical Research, Eisai Inc.

GEORGE KOOB, Director, National Institute on Alcohol Abuse and Alcoholism

WALTER KOROSHETZ, Director, National Institute of Neurological Disorders and Stroke

ROBERT MALENKA, Pritzker Professor of Psychiatry, Stanford University

HUSSEINI MANJI, Professor, Oxford University; Visiting Professor, Duke University; Co-Chair, UK Government Mental Health Mission

HUGH MARSTON, Senior Vice President and Head of Global CNS Discovery, Boehringer Ingelheim

BILL MARTIN, Global Therapeutic Area Head, Neuroscience, The Janssen Pharmaceutical Companies of Johnson & Johnson

JOHN NGAI, Director, BRAIN Initiative

GENTRY PATRICK, Professor of Neurobiology, University of California, San Diego

STEVE MARC PAUL, CEO and Chairman, Karuna Therapeutics, Inc.

KATHRYN RICHMOND, Executive Vice President, Director, Frontiers Group and Office of Science and Innovation, Allen Institute

M. ELIZABETH ROSS, Nathan Cummings Professor, American Neurological Association

MARSIE ROSS, Director, Head of Alliance Development and Public Policy, Harmony Biosciences

KATIE SALE, Executive Director, American Brain Coalition

RAYMOND SANCHEZ, Chief Medical Officer, Cerevel Therapeutics

TERRENCE SEJNOWSKI, Francis Crick Professor, Salk Institute for Biological Studies

SARAH SHEIKH, Senior Vice President, Neuroscience, Takeda Pharmaceutical

SARAH SHNIDER, Scientific Director, One Mind

DAVID SHURTLEFF, Deputy Director, National Center for Complementary and Integrative Health

JOHN SPIRO, Senior Vice President & Senior Scientist, Simons Foundation

ALESSIO TRAVAGLIA, Director, Neuroscience, Foundation for the National Institutes of Health

NORA VOLKOW, Director, National Institute on Drug Abuse

DOUG WILLIAMSON, Executive Vice President, Acadia Pharmaceuticals

RICHARD WOYCHIK, Director, National Institute of Environmental Health Sciences

STEVIN ZORN, President and CEO, MindImmune Therapeutics, Inc.

Forum on Neuroscience and Nervous System Disorders Staff

SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders

EVA CHILDERS, Associate Program Officer

MAYA THIRKILL, Associate Program Officer

EDEN NELEMAN, Senior Program Assistant (until August 2023)

KIMBERLY OGUN, Senior Program Assistant

CLARE STROUD, Senior Director, Board on Health Sciences Policy

Reviewers

This Proceedings of a Workshop 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 proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.

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

HAYLA K. SLUSS, University of Massachusetts Chan Medical School

ALEXANDRA B. YONTS, Children’s National Hospital

ILENE S. RUHOY, Mt. Sinai South Nassau, Chiari Center

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by DIANE E. GRIFFIN, Johns Hopkins University. She was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.

Contents

ACRONYMS AND ABBREVIATIONS

1 INTRODUCTION

Organization of the Workshop

Organization of the Proceedings

2 OVERVIEW OF INFECTION-ASSOCIATED CHRONIC ILLNESSES

Sponsor Remarks

Common Ground Across Infection-Associated Chronic Illnesses

A Historical Perspective

Stakeholder Perspectives

Discussion

3 COMMON MECHANISTIC FACTORS OF INFECTION-ASSOCIATED CHRONIC ILLNESSES

Host-Mediated Factors

Pathogen-Mediated Factors and Pathogen Persistence

4 POTENTIAL RESEARCH PRIORITIES AND OPPORTUNITIES IN DIAGNOSTICS

Using Biomarkers for Diagnosis

Using Microclots as Indicators of Disease

Next-Generation and Metagenomic Sequencing

Discussion

5 POTENTIAL RESEARCH PRIORITIES AND OPPORTUNITIES IN THERAPEUTICS

Antiviral Development

Clinical Trials for Multisystem Inflammatory Syndrome in Children and Long COVID

Opportunities for Prevention and Treatment of Lyme Disease Associated Chronic Illnesses

Clinical Care Across Illnesses

Discussion

6 ADVANCING RESEARCH FOR INFECTION-ASSOCIATED CHRONIC ILLNESSES

Perspective from the Food and Drug Administration

Patient-Driven Research

Research Innovation and Required Infrastructure

7 CONSIDERING CHALLENGES AND OPPORTUNITIES IN A SHARED RESEARCH AGENDA

Remaining Challenges and Future Directions

Discussion

APPENDIXES

A REFERENCES

B WORKSHOP STATEMENT OF TASK

C WORKSHOP AGENDA

Boxes and Figures

BOXES

6-1 Suggestions for Future Research Priorities

7-1 Suggestions from Individual Speakers

FIGURES

1-1 Potential mechanisms for infection-associated chronic illnesses

2-1 Relationship between abnormalities

3-1 Proposed mechanisms of long COVID

3-2 Differential effects of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in long COVID

3-3 Dysbiotic microbiome-immune interactions

4-1 Serum CCL19 levels over time correlated to clinical outcome status

4-2 Pathological clotting

4-3 A microclot grading system

5-1 Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier

5-2 Health and disease manifestations affected by the microbiome

6-1 Female reproductive conditions in long COVID (LC), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), and Ehlers-Danlos syndrome (EDS)

7-1 Chronic neurological sequelae of COVID-19

Acronyms and Abbreviations