CRITICAL NEEDS AND GAPS IN UNDERSTANDING PREVENTION, AMELIORATION, AND RESOLUTION OF LYME AND OTHER TICK-BORNE DISEASES

The Short-Term and Long-Term Outcomes

WORKSHOP REPORT

Committee on Lyme Disease and Other Tick-Borne Diseases: The State of the Science

Board on Population Health and Public Health Practice

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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CRITICAL NEEDS AND GAPS IN UNDERSTANDING PREVENTION, AMELIORATION, AND RESOLUTION OF LYME AND OTHER TICK-BORNE DISEASES The Short-Term and Long-Term Outcomes WORKSHOP REPORT Committee on Lyme Disease and Other Tick-Borne Diseases: The State of the Science Board on Population Health and Public Health Practice

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract No. N01-OD-4-2139 between the National Academy of Sciences and the National Institutes of Health. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not neces- sarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-21109-3 International Standard Book Number-10: 0-309-21109-3 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www. iom.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover images courtesy of the Centers for Disease Control and Prevention’s Public Health Image Library. IOM (Institute of Medicine). 2011. Critical needs and gaps in understanding prevention, ame- lioration, and resolution of Lyme and other tick-borne diseases: The short-term and long-term outcomes: Workshop report. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding en- gineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON LYME DISEASE AND OTHER TICK-BORNE DISEASES: THE STATE OF THE SCIENCE LONNIE J. KING, D.V.M. (Chair), Dean, College of Veterinary Medicine, The Ohio State University, Columbus, OH NAOMI L. GERBER, M.D., Director, Center for the Study of Chronic Illness & Disability, George Mason University, Fairfax, VA STEPHEN M. OSTROFF, M.D., Director, Bureau of Epidemiology, Pennsylvania Department of Health, Harrisburg, PA GUY H. PALMER, D.V.M., Ph.D., Regents Professor of Pathology and Infectious Diseases; The Creighton Chair and Director of the School for Global Animal Health, Washington State University, Pullman, WA GORDON E. SCHUTZE, M.D., Professor and Vice-Chairman for Educational Affairs, Department of Pediatrics, Vice President, Baylor International Pediatric AIDS Initiative, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX DAVID H. WALKER, M.D., The Carmage and Martha Walls Distinguished University Chair in Tropical Diseases, Professor and Chair, Department of Pathology, Executive Director, Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch-Galveston, Galveston, TX Study Staff CHRISTINE M. COUSSENS, Ph.D., Senior Program Officer and Study Director, Board on Population Health and Public Health Practice CAROL MASON SPICER, Ph.D., Associate Program Officer, Board on Population Health and Public Health Practice (from December 2010) RITA DENG, M.H.S., Associate Program Officer, Board on Population Health and Public Health Practice (until October 2010) TREVONNE WALFORD, B.S., Research Assistant, Board on Population Health and Public Health Practice PAM LIGHTER, B.S., Senior Program Assistant, Board on Population Health and Public Health Practice (until April 2010) HOPE HARE, M.A., Adminstrative Assistant, Board on Population Health and Public Health Practice ANDREA BANKOSKI, M.P.H., Consultant SANDRA HACKMAN, B.A., Consultant ROSE MARIE MARTINEZ, Sc.D., Director, Board on Population Health and Public Health Practice PATRICK KELLEY, M.D., Director, Board on Global Health v

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Reviewers This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: Abdu F. Azad, Pharm.D., Ph.D., M.P.H., Professor of Microbiology and Immunology, University of Maryland Stephen W. Barthold, D.V.M., Ph.D., Professor of Pathology and Director of the Center of Comparative Medicine, University of California at Davis Linda Lobes, Director, Michigan Lyme Disease Association Robert Smith, M.D., M.P.H., Maine Medical Center Research Institute Ellen Stromdahl, Ph.D., Entomologist, US Army Public Health Command Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not see the final draft of the vii

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viii REVIEWERS report before its release. The review of this report was overseen by Linda McCauley, Ph.D., F.A.A.N., R.N., Dean, Nell Hodgson Woodruff School of Nursing, Emory University. Appointed by the National Research Council, she was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Contents Preface: A Walk in the Woods xi Acronyms xv Overview 1 1 Introduction 7 2 An Overview of Tick-Borne Diseases 15 3 The Social Construction and Human Face of Tick-Borne Disease 25 4 Emerging Infections, Tick Biology, and Host–Vector Interactions 37 5 Surveillance, Spectrum, and Burden of Tick-Borne Disease, and At-Risk Populations 61 6 Pathogenesis 97 7 Diagnostics and Diagnosis 125 8 Prevention 155 9 Closing Panels 177 References 193 APPENDIXES A Commissioned Papers 219 B Federal Funding of Tick-Borne Diseases 497 C Summary of Public Comment on Agenda 509 D Workshop Agenda 515 E Public Comment Summary 525 F Speaker Biosketches 531 ix

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Preface: A Walk in the Woods Lyme disease and many other tick-borne diseases (TBDs) are zoonotic diseases in which a pathogen moves from an animal host to a person through ticks. Scientists now understand the complexities associated with such disease transmissions, including the role of ecosystems as it relates to the life cycle of the pathogen. A walk in the woods in certain geographic areas of the United States constitutes a risk factor for exposure to Lyme disease or other tick-borne illness. The same phrase, a “walk in the woods,” is also a metaphor for a process of conflict resolution. A “walk in the woods” is a model named for the classic 1982 saga of two Cold War nuclear arms reduction negotiators from the United States and Russia who broke an impasse in their talks by accompanying each other for a walk in the woods around Geneva, Swit- zerland, leading them to new insights and compromise, and ultimately a newly crafted agreement based on shared interests. This saga was later im- mortalized in a Broadway play symbolizing the advantage of interpersonal bargaining and interest-based negotiation. It was obvious to participants at the workshop that a significant im- passe has developed in the world of Lyme disease. There are conflicts within and among the science; policy; politics; medicine; and professional, public, and patient views pertaining to the subject, which have created significant misunderstandings, strong emotions, mistrust, and a game of blaming oth- ers who are not aligned with one’s views. Lines in the sand have been drawn, sides have been taken, and frustration prevails. The “walk in the woods” process of conflict resolution or a similar process seems necessary xi

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xii PREFACE for creating a new environment of trust and a better environment for more constructive dialogue to help focus research needs and achieve better outcomes. Such a process does not imply a compromise of the science but rather is needed to shift to a more positive and productive environment to optimize critical research and promote new collaborations. Pamela Weintraub spoke eloquently about her personal experience and her family’s challenges with Lyme disease. Ms. Weintraub also made the point that the impasses and mistrust that exist have been instrumental in impeding progress toward developing solutions by creating an environment that is unproductive and even accusatory. Thus, a “walk in the woods” seems to be in order not only in considering factors in disease transmission but also as a process by which to find common ground, align interests, and develop a national strategy to address the complex and serious issues of TBD, including Lyme disease. The committee believes that the project will provide a snapshot of the state of the science for TBDs, but it recognizes that not all topics could be covered in as much depth during a 2-day workshop as would be satisfying to the committee or the scientific community. Furthermore, the committee was cognizant of the societal issues that could affect the scientific agenda, but we did not allow the controversy to affect the scientific discussion. Dur- ing the process, the committee also noted a lack of precision in describing research. In the report, the committee has not attempted to impose uniform terminology or definitions, opting to retain those employed by the individ- ual speakers. The committee realizes that the lack of precise, uniform ter- minology is hampering the reporting and the discussions of stages of Lyme disease and other tick-borne diseases. Although the committee was not charged to produce recommendations, we hope that this body of work will result in further discussions of research gaps, opportunities, and priorities. Many individuals and organizations contributed to this report. The committee thanks the authors of the commissioned papers, who worked diligently over the summer and the early fall to produce the extensive back- ground that contributed to discussions at the workshop. The committee also thanks the presenters at the workshop, the members of the research community, and the public who shared their perspectives before and during the meeting, as well as the many individuals who participated in other pub- lic forums, on phone calls, and by e-mail. We understand and appreciate the negative impact that some of these diseases have on the quality of peoples’ lives. The convergence of science with real-life situations has highlighted both the need for more scientific knowledge and the serious societal issues and challenges that need to be addressed through scientific advancements. The committee also extends its thanks to Sandra Hackman for provid- ing preliminary drafts of some of the presentations; to Trevonne Walford for ensuring that the meetings and listening sessions ran smoothly and

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xiii PREFACE providing research and writing support; to Pam Lighter for assisting with the committee formation and background information; to Rita Deng for collecting initial data on the federal programs; to Andrea Bankoski for analyzing the federal program data; and to Carol Mason Spicer for drafting sections of the report and helping to provide critical comments. Hope Hare was instrumental in preparing the document for review and publication. We also thank Christine M. Coussens, who was the study director for the project. Together with Rose Marie Martinez, the board director, Christine helped the committee navigate the sociobiology issues. Although this was a challenging assignment, the committee welcomed the opportunity to help improve understanding of this group of diseases and, more importantly, to improve the lives of those who have been profoundly impacted by them.

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Acronyms ACA Acrodermatitis chronica atrophicans ADNI Alzheimer’s Disease Neuro-Imaging Initiative AHSV African horse sickness virus ALS Amyotrophic lateral sclerosis ANA Antinuclear antibodies APC Antigen-presenting cell Arp Arthritis-related protein CALDA California Lyme Disease Association CBC Complete blood count CCHF Crimean-Congo hemorrhagic fever CCHFV Crimean-Congo hemorrhagic fever virus CDC Centers for Disease Control and Prevention CF Complement fixation CFS Chronic fatigue syndrome CME Canine monocytic ehrlichosis CRASP Complement regulator-acquiring surface protein CRF Case report form CSF Cerebrospinal fluid CSTE Council of State and Territorial Epidemiologists DbhA DNA-binding protein HU-alpha Dbp Decorin-binding protein DC Dense-cored cell xv

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xvi ACRONYMS DFA Direct fluorescent antibody DGGE Denaturing gradient gel electrophoresis DNA Deoxyribonucleic acid ECCMID European Conference on Clinical Microbiology and Infectious Diseases ECDC European Centre for Disease Control EEE Ehrlichia ewingii ehrlichiosis EIA Enzyme immunoassay ELISA Enzyme-linked immunosorbent assay EM Erythema migrans ESCMID European Society of Clinical Microbiology and Infectious Diseases EST Expressed sequence tag EUCALB European Union Concerted Action on Lyme Borreliosis FDA Food and Drug Administration FISH Fluorescent in situ hybridization GIS Geographic Information Systems HA Human anaplasmosis HBV Hepatitis B virus HCV Hepatitis C virus HE Human granulocytic ehrlichiosis HEE Human ehrlichosis ewingii HGA Human granulocytic anaplasmosis hgt Horizontal gene transfer HIV Human immunodeficiency virus HME Human monocytic ehrlichiosis HPA Hypothalamic–pituitary–adrenal Hsps Heat-shock protein genes IDSA Infectious Diseases Society of America IFA Immunofluorescence assay IFAT Indirect immunofluorescence IFN Interferon IFN- Interferon gamma IgG Immunoglobulin G IgM Immunoglobulin M IHA Indirect hemagglutination

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xvii ACRONYMS IL Interleukin ILADS International Lyme and Associated Diseases Society IOE Ixodes ovatus Ehrlichia IOM Institute of Medicine KFD Kyasanur forest disease LA Latex agglutination LD Lyme disease LFA-1 Lymphocyte function associated antigen LPS Lipopolysaccharide LTT Lymphocyte transformation MA Microagglutination MHC Major histocompatibility complex MLST Multilocus sequence typing MRI Magnetic resonance imaging MSF Mediterranean spotted fever MSP Major surface protein NatCapLyme National Capital Lyme and Tick-borne Disease Association NDVI Normalized difference vegetation index NEDSS National Electronic Disease Surveillance System National Electronic Telecommunications System for NETSS Surveillance NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NIP Nymphal infection prevalence NK Natural killer NKT Natural killer T NNDSS National Notifiable Disease Surveillance System NSAIDs Non-steroidal anti-inflammatory drugs OMP Outer membrane protein Osp Outer surface protein PCR Polymerase chain reaction PFGE Pulsed-field gel electrophoresis PLS Post-Lyme syndrome POTS Postural orthostatic tachycardia syndrome RC Reticulate cell RELU Rural Economy and Land Use

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xviii ACRONYMS RMSF Rocky Mountain spotted fever Sca Stem cell antigen SCID Severe combined immunodeficiency SFG Spotted fever group SNP Single-nucleotide polymorphism STARI Southern tick-associated rash illness TBD Tick-borne diseases TBE Tick-borne encephalitis TFSS, T4SS Type IV secretion system TG Typhus group TIBOLA Tick-borne lymphdenopathy TLR Toll-like receptor T-RFLP Terminal restriction fragment length polymorphisms TRP Tandem repeat protein TRs Tandemly repeated sequences VBD Vector-borne disease VMP Variable membrane protein WHO World Health Organization WTD Whitetail deer