Charting a Path Toward New Treatments for Lyme Infection-Associated Chronic Illnesses (2025)
Chapter: Front Matter
Consensus Study Report
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This activity was supported by contracts between the National Academy of Sciences and the Steven & Alexandra Cohen Foundation. 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.
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COMMITTEE ON THE EVIDENCE BASE FOR LYME INFECTION-ASSOCIATED CHRONIC ILLNESSES TREATMENT
KENT E. KESTER (Chair), Coalition for Epidemic Preparedness Innovations
JOHN A. BRANDA, Harvard Medical School
BETTY A. DIAMOND, Feinstein Institute for Medical Research, Northwell Health
JESSE L. GOODMAN, Georgetown University
MIGUEL A. HERNÁN, Harvard T.H. Chan School of Public Health
ADRIAN F. HERNANDEZ, Duke School of Medicine; Duke Clinical Research Institute
BRANDON L. JUTRAS (resigned from the committee September 2024), Northwestern Feinberg School of Medicine
NICOLE MALACHOWSKI, Nicole Malachowski & Associates, LLC
CHERIE MARVEL, Johns Hopkins University School of Medicine
DEBJANI MUKHERJEE, Weill Cornell Medical College
LISE E. NIGROVIC, Boston Children’s Hospital
SIMONE A. SEWARD, SUNY Upstate Medical University
ROBERT P. SMITH, MaineHealth Institute for Research; Tufts University School of Medicine
QING MEI WANG, Harvard Medical School
SUSAN J. WONG, Wadsworth Institute, New York State Department of Health (retired June 2020)
Study Staff
JULIE LIAO, Study Co-Director
ANDREW MARCH, Study Co-Director
EMILY MCDOWELL, Research Associate
RAYANE SILVA-CURRAN, Senior Program Assistant
REBECCA MORGAN, Senior Research Librarian
CAROLYN SHORE, Global Health Lead and Senior Program Officer (as of January 2025)
JULIE PAVLIN, Director, Board on Global Health
CLARE STROUD, Director, Board on Health Sciences Policy
Consultants
AMINA QUTUB, University of Texas, San Antonio
MAARTJE WOUTERS, Medical and Science Writer
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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:
DAVID ALLISON, Indiana University
HUGH AUCHINCLOSS, National Institutes of Health (retired)
JOHN AUCOTT, Johns Hopkins University
JEANNE BERTOLLI, Centers for Disease Control and Prevention (retired)
CHARLES CHIU, University of California, San Francisco
CAROLYN COMPTON, Arizona State University
ROBERTA DEBIASI, Children’s National Hospital
MAGDIA DE JESUS, Pfizer
MICHAEL IADEMARCO, U.S. Public Health Service (retired)
LORRAINE JOHNSON, LymeDisease.org
AKIKO IWASAKI, Yale University; Howard Hughes Medical Institute
SERENA SPUDICH, Yale University
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 PAUL VOLDBERDING, University of California, San Francisco, and ENRIQUETA BOND, Burroughs Wellcome Fund. 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.
Acknowledgments
The committee would like to express its gratitude to the many individuals and organizations that made this report possible. First, the committee would like to thank the Steven & Alexandra Cohen Foundation for sponsoring this study.
The committee is greatly indebted to the individuals who, through their generous contributions of time and expertise, informed this report over the course of the committee’s open meetings. A full list of those individuals can be found in the meeting agendas, reproduced in Appendix A. The committee is particularly appreciative of the numerous individuals living with Lyme infection-associated chronic illnesses (IACI) and advocates who participated in the committee’s meetings and had the impossible task of communicating the true toll of Lyme IACI.
The committee also thanks Amina Qutub for providing a critical analysis of the potential of artificial intelligence in advancing Lyme IACI research. The scoping review that the committee conducted would not have been possible without the methodological and operational guidance from the team at PICO Portal, including Eitan Agai, Renee Wilson, Alon Agai, Ahmed Elmoghazy, Rodrigo Conde, Stephanie Qureshi, Olabisi Oduwole, Ramesh Bhandari, and Riaz Qureshi.
Finally, this report is only possible thanks to the dedication of the staff at the National Academies of Sciences, Engineering, and Medicine. The study team of Julie Liao, Andrew March, Emily McDowell, and Rayane Silva-Curran provided the committee guidance and support throughout
the process. Greysi Patton, finance business partner; Lori Brenig, editorial projects coordinator; Leslie Sim, senior report review officer; Taryn Young, report review associate; Marguerite Romatelli, communications specialist; and others in the Health and Medicine Division Executive Office, Office of the Chief Communications Officer, and Office of Congressional and Government Affairs assisted this study as well. And the committee extends its thanks to Maartje Wouters for her adept skills in contributing to the writing and editing of the report and to Robert Pool for his editorial assistance.
Evidence on the Treatment of Lyme IACI
Evidence on the Mechanisms of Lyme IACI
Evidence on the Diagnosis of Lyme IACI
Key Questions for Future Research
3 BUILDING ON RESEARCH FROM OTHER INFECTION-ASSOCIATED CHRONIC ILLNESSES
Clinical Evidence on Symptom-Based Approaches to Treatments for IACI
Opportunities for Translating Promising Approaches to Lyme IACI
4 INNOVATIVE APPROACHES TO ACCELERATING LYME IACI RESEARCH
A Common Framework to Prioritize Lyme IACI Research
Considerations for Implementation
Research into New Treatments That Alleviate Symptoms
Standardized Research Definitions and Metrics
Improved Access to Biobanks and Registries
Coordinated Research Funding and Collaboration Efforts
Collaboration Across IACI Research
Boxes, Figures, and Tables
BOXES
S-1 Key Questions for Future Research
1-3 Operational Scope of Lyme IACI
1-4 A Critical Need and Opportunity
2-1 Definition of Post-Treatment Lyme Disease Syndrome
3-1 Developing Effective Treatments to Mitigate Symptoms: Case Study with Fibromyalgia
3-2 Applying New Research Tools to Lyme IACI: A Case Study on Neuroscience
4-1 Ongoing Longitudinal Observational Studies in Lyme IACI in the U.S.
FIGURES
S-2 Peer-reviewed Lyme IACI research, 1970–May 2024
S-3 Framework for prioritization of potential Lyme IACI treatments for clinical trials
1-3 Relationship between the etiology, pathogenesis, and symptoms for Lyme IACI
2-1 Flowchart of articles screened for and included in the scoping review
2-3 Study designs of published Lyme IACI treatment trials
2-4 Proposed mechanisms of Lyme IACI in published literature
3-1 NIH funding for Lyme Disease research, 2008–2025
4-1 Framework for research prioritization of Lyme IACI treatment interventions
TABLES
2-1 Summary of Prospective Studies Reviewing the Prevalence of PTLDS
2-2 Key Study Characteristics from Randomized Trials
2-3 Study Designs of Publications in Scoping Review on Lyme IACI Mechanisms
4-1 Example of Applying Prioritization Assessment of Lyme IACI Treatment Interventions
C-1 Keywords Used to Describe Lyme IACI for Title and Abstract Literature Search
C-2 Inclusion and Exclusion Criteria for Abstracts Screening
C-3 Inclusion and Exclusion Criteria for Full-Text Screening
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Preface
While the causes of Lyme infection-associated chronic illnesses (IACI) remain uncertain, it is clear that patient symptoms are deserving of improved diagnosis and treatment, especially in this era of significant advances in medical science. This is the underlying reason for this consensus study—to evaluate and call attention to the existing evidence base associated with Lyme IACI and in doing so, help to frame the gaps in knowledge and the potential for innovative approaches to better understand, diagnose, and treat these diverse sequelae of Lyme disease.
In spite of myriad advances in the diagnosis and treatment of infectious diseases and their complications, Lyme disease, in many ways, remains an outlier. Whether related to an incomplete understanding of its epidemiology, imprecise and sometimes unvalidated diagnostic tests, or potentially suboptimal therapies for the infection, Lyme disease continues to bedevil clinicians and patients alike. A particularly important and poorly understood aspect of Lyme disease is its association with a variety of symptoms that persist post-infection and post-treatment, such as “brain fog” (characterized by difficulties in concentration and memory changes), sleep disturbances, systemic fatigue and weakness, or unexplained pain syndromes. Unfortunately, there is limited understanding of the pathophysiology of such persistent symptoms, and there are no validated diagnostic and therapeutic modalities. As a result, patients presenting with Lyme IACI and their health care providers lack access to well-defined, evidence-based, and commonly accepted standards to support either clear, consistent diagnosis or effective treatment.
This gap has led not only to continuing symptoms and disability for many people but also to a variety of unvalidated treatment regimens, some of which may carry great harm for patients. Owing to this, patients with Lyme IACI continue to be frustrated with uncertain or inconsistent diagnoses and treatments that in many cases do not improve their symptoms and quality of life. While there has been a fair amount of clinical research conducted into optimizing antibiotic treatment of well-defined Lyme disease entities associated with active infection, from erythema migrans to arthritis, much less effort and funding support has been dedicated to exploring the diverse Lyme IACI in terms of either diagnosis or treatment.
In the aftermath of the COVID-19 pandemic, we have seen the striking emergence of diverse symptoms and other findings considered under the umbrella of Long COVID in substantial numbers of patients after a SARS-CoV-2 infection. And while Long COVID may differ from Lyme IACI in many ways, there are a number of similar, overlapping symptoms, suggesting commonalities of the underlying pathophysiologic processes in the host. This parallel, along with other IACI syndromes, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), was the subject of a National Academies Forum on Microbial Threats workshop in 2023. The workshop highlighted data supporting hypotheses suitable for further investigation for understanding the pathophysiology of various IACI and exploring possible approaches to treatment. Notably, significant National Institutes of Health (NIH) funding has been allocated to study this newly recognized complication of SARS-CoV-2 infection. However, and in spite of the much longer timeline since the diverse chronic complications associated with Lyme disease were identified, limited NIH research support has so far been focused on Lyme IACI. Given the continued expansion of tickborne disease across the United States, there is an urgent need for improved treatment of Lyme IACI. In this era of incredible technological advances in clinical medicine, the needed improvements are within our reach.
On behalf of the entire committee and the National Academies’ project staff, I would like to thank the many patients, scientists, and advocates who provided input into this report. I especially want to highlight the role and contributions of patients with Lyme IACI, as they often continue to suffer persisting symptoms and, in many cases, work to call attention to the need for better treatments. We also thank the reviewers for their useful feedback as well as the monitor and coordinator who oversaw the report review.
This report would not have been possible without the incredible support of the talented National Academy staff, including the study co-directors Julie Liao and Andrew March, along with Emily McDowell, Rayane Silva-Curran, Rebecca Morgan, and Khiara Reed.
In the end, we hope that this report has real impact on the future of Lyme IACI research and the lives of people living with the syndrome. The goal of this report is to effectively highlight those areas of medical innovation that can be applied to address and ultimately treat the multitude of current and future patients who suffer with Lyme IACI. Our patients deserve better.
Kent E. Kester, M.D., Chair
Committee on the Evidence Base for Lyme
Infection-Associated Chronic Illnesses Treatment
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Acronyms and Abbreviations
| AHRQ | Agency for Healthcare Research and Quality |
| AI | artificial intelligence |
| CBT | cognitive behavioral therapy |
| CDC | Centers for Disease Control and Prevention |
| CDE | common data element |
| CDMRP | Congressionally Directed Medical Research Programs |
| CLIA | Clinical Laboratory Improvement Amendments |
| CNS | central nervous system |
| CSF | cerebral spinal fluid |
| CTN | Clinical Trials Network |
| ELISA | enzyme-linked immunosorbent assay |
| EM | erythema migrans |
| FDA | U.S. Food and Drug Administration |
| fMRI | functional magnetic resonance imaging |
| HHS | Department of Health and Human Services |
| IACI | infection-associated chronic illnesses |
| ICD | International Classification of Diseases |
| IDSA | Infectious Diseases Society of America |
| IND | investigational new drug |
| IRB | Institutional Review Board |
| LD | Lyme disease |
| LLM | large language model |
| MCID | minimal clinically important difference |
| ME/CFS | myalgic encephalomyelitis/chronic fatigue syndrome |
| ML | machine learning |
| NADH | Nicotinamide adenine dinucleotide (reduced) |
| NGS | next-generation sequencing |
| NIAID | National Institute of Allergy and Infectious Diseases |
| NIH | National Institutes of Health |
| NINDS | National Institute of Neurological Disorders and Stroke |
| PCORI | Patient-Centered Outcomes Research Institute |
| POTS | postural orthostatic tachycardia syndrome |
| PRO | patient-reported outcome |
| PTLDS | post-treatment Lyme disease syndrome |
| QoL | quality of life |
| RWD | real-world data |
| RWE | real-world evidence |
| STARI | southern tick-associated rash illness |
| TBDWG | Tick-Borne Disease Working Group |
| tDCS | transcranial direct current stimulation |
| VNS | vagus nerve stimulation |
Glossary
Biobank: A collection of biological specimens and associated data suitable for research purposes.
Clinical trial: A study in which researchers assign individuals to specific interventions, which can be a therapeutic, diagnostic, medical device, or procedure to evaluate the safety and efficacy of the intervention.
Common data element (CDE): A standardized, precisely defined question that is paired with a set of specific allowable responses, that is then used systematically across different sites, studies, or clinical trials to ensure consistent data collection.
Control group: A group of individuals in a study who are assigned to receive a placebo or alternative treatment to the intervention of interest, or who do not exhibit a particular variable of interest. The control group serves as a comparison to the group receiving the intervention or the group exhibiting the particular variable of interest.
Etiology: The cause or origin of a disease.
Infection-associated chronic illnesses (IACI): Diseases or syndromes with a potential root cause in infections, encompassing some conditions where the etiology remains unknown but have been documented to include infectious
triggers. Examples are Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Lesion: An area of abnormal or damaged tissue caused by injury, infection, or disease. A lesion can occur anywhere in or on the body, such as the skin, blood vessels, brain, and other organs.
Negative predictive value: The probability that a negative test result correctly rules out the disease or condition for an individual in the given population.
Objective outcome measures: Quantifiable data that can be measured to minimize the potential influence of human bias from the study participant, researcher, or other observer. Objective measures are gathered using standardized tools and procedures. These may include laboratory tests, imaging studies and interpretations, physical examinations, and other clinical findings.
Observational studies: Studies in which researchers do not assign participants to receive interventions but rather observe the participants for outcomes of interest and compare them to participant factors, including use of a particular treatment. As a result, determining causation is difficult as outcomes could be due to the variable of interest, or to inherent participant factors that influence the distribution of the variable within the population.
Pathogenesis: The mechanisms by which a disease develops, progresses, and either persists or is resolved.
Pathophysiology: The functional and biochemical changes that are associated with or result from disease or injury.
Patient registry: An organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves a predetermined scientific, clinical, or policy purpose.
Positive predictive value: The probability that a positive test result correctly identifies a case of the disease or condition in a given population.
Prospective studies: Studies in which data are collected in chronological order. All randomized trials are prospective studies.
Randomization: The process by which interventions are randomly assigned to study participants in a clinical trial to reduce the influence of inherent participant characteristics.
Rash: An area of the skin that has changes in texture or color and may look inflamed or irritated. The skin may be red, warm, scaly, bumpy, dry, itchy, swollen, or painful. It may also crack or blister. A rash can occur in one area of the body or all over the body and may look very different depending on the cause.
Retrospective studies: Data on treatments are collected after the outcomes have occurred. Some observational studies are retrospective.
Sensitivity: The sensitivity of a test refers to its ability to correctly identify individuals who have the target disease or condition. Few true positive cases are missed if a diagnostic test has high sensitivity.
Specificity: The specificity of a test refers to how likely it is to correctly return a negative result in people who do not have the target disease or condition. Tests with high specificity return few false-positive results.
Subjective outcome measures: Self-reported data obtained from study participants or researchers. These can be obtained using surveys or interviews and may include self-assessments of quality of life or pain severity.
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