Perspectives on “Chronic Lyme Disease”

Lyme disease is an infection caused by Borrelia burgdorferi sensu lato, which is transmitted to humans through the bite of an infected Ixodes tick. The majority of patients recover without complications with antibiotic therapy. However, for a minority of patients, accompanying non-specific symptoms can persist for months following completion of therapy. The constellation of symptoms such as fatigue, cognitive dysfunction, and musculoskeletal pain that persist beyond 6months and are associated with disability have been termed post-treatment Lyme disease syndrome (PTLDS), a subset of a broader term "chronic Lyme disease." Chronic Lyme disease is a broad, vaguely defined term that is used to describe patients with non-specific symptoms that are attributed to a presumed persistent Borrelia burgdorferi infection in patients who may or may not have evidence of either previous or current Lyme disease. The diagnoses of chronic Lyme disease and of PTLDS have become increasingly relevant to the practice of immunologists due to referrals for consultation or for intravenous immunoglobulin (IVIG) treatment. This review aims to explore the relationship between chronic Lyme disease, post-treatment Lyme disease syndrome, and the immune system. Here, we review the current literature on (1) issues in conventional and alternative diagnostic testing for Lyme disease, (2) the hypothesis that B. burgdorferi infection can persist despite appropriate use of recommended antibiotics, (3) current theories regarding B. burgdorferi's role in causing both immune dysregulation and protracted symptoms, and (4) the use of IVIG for the treatment of Lyme disease.

Lyme disease (LD) is a multisystemic disease without a current approved human vaccine. Increasing infection rates have created pressure to improve the diagnosis and treatment of LD in Canada. This study aims to inform LD care through the exploration of health care practitioner (HCP) perspectives, experiences, beliefs, and knowledge of LD diagnosis and treatment. Canadian HCPs took part in bilingual (English and French) semi-structured interviews to explore their experiences and perspectives related to LD diagnosis and treatment. Major themes within and between participants were identified using inductive thematic analysis and axial coding. A total of 43 HCPs working in LD-related fields participated in this study. Four major themes were identified; HCPs have: 1) Similar perspectives regarding antibiotic use, regional influences, and physician referral; 2) diverse perspectives on the use of serology testing and barriers for LD diagnosis and treatment between endemic and nonendemic regions; 3) challenges and disagreement toward diagnosing and treating chronic LD; and 4) trust in one (among several) LD guidelines, yet consult a variety of secondary sources for additional LD knowledge. The findings reveal a pressing need for greater consistency among HCPs regarding the diagnosis and treatment of LD in Canada. Variation can be attributed to diverse beliefs, perspectives, and approaches within LD practitioners generally, but is particularly evident when addressing, acknowledging, and defining chronic LD.

Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.

Lyme borreliosis is a world-wide multi-organic disease caused by spirochete Borrelia burgdorferi sensu lato. Numerous gene-species Borrelia are identified with a various frequency in Europe, Asia and America (Ruderko, et al., 2009; Siegel, et al., 2008; Stanek G, 2011; Wilske, et al., 2007 Wodecka, 2006a). Within the last few years, as well as in Europe as in North America, there were prepared strategies, directives and guidelines for diagnostics and treatment of Lyme disease, including the frequency of occurrence of specific genespecies and a specification of clinical symptoms (Center for Disease Control and Prevention [CDC], 2011; European Concerted Action on Lyme Borreliosis [EUCALB], 2008). Lyme disease seems to be easy to diagnose and treat due to the pathogenic factor known for a long-time and elaborated diagnostic and therapeutic schemas. In serological diagnostics an impediment constitutes a wide range of genospecies B. burgdorferi, changes of expression of particular genes occurring in various stages of an infection, and cross reactions which occur in the presence of other pathogenic microorganisms and disease entities connected with an immune response disorders. It is connected with the necessary use of appropriately configured diagnostic tests and recombinant proteins common for particular genospecies and related to the immunological response at different stages of the infection (EUCALB, 2008; Zajkowska, et al., 2006a,2006b). As well as a diagnostician as a doctor has to consider not only the results of the serological tests but also numerous, coexisting, frequently unspecified factors in order to make an accurate diagnose confirming or excluding B. burgdorferi infection. In many cases, even early and accurate diagnosis and antibiotic therapy appropriately applied does not guarantee the effective eradication of a pathogen, and what is important for a patient a complete elimination of symptoms of the disease. Posttreatment Lyme disease Syndrome (PTLDS) has been confirmed in some patients – it is a complex of lingering, unspecified clinical symptoms which impede a complete physical and mental recovery in patients after being treated from Lyme disease. This is a crucial problem as well as in health as in social life which is frequently ignored. The symptoms concerning Lyme arthritis and neuroborreliosis are frequently the cause of an immense disability in patients in numerous life activities and it is required to undertake a rehabilitation program (Tokarska-Rodak et al., 2007).

Lyme disease, which is caused by the tickborne spirochete Borrelia burgdorferi, is estimated to cause over 300 000 cases annually in the United States, primarily in northeastern and mid-Atlantic States [1]. In untreated patients, the infection typically occurs in stages with different manifestations at each stage [2]. It usually begins during summer with an expanding skin lesion, erythema migrans, sometimes followed weeks later by neurologic or cardiac abnormalities, and often followed months later by arthritis, or rarely a subtle encephalopathy or polyneuropathy. With late stage abnormalities, patients often have few, if any, systemic symptoms. Most patients respond well to appropriate antibiotic regimens for the stage of disease, as recommended by the Infectious Diseases Society of America (IDSA) [3]. However, despite antibiotic therapy, some patients experience post-infectious signs or symptoms, which can be quite disabling. The only post-infectious picture with a well-defined pathologic correlate (proliferative synovitis) is antibiotic-refractory Lyme arthritis [4]. In such patients, inflammatory arthritis persists for months or several years after apparent spirochetal killing with oral and intravenous (IV) antibiotics. Excessive inflammation, immune dysregulation, and infectioninduced autoimmunity are thought to play a role in this disease outcome [5]. After antibiotic therapy, treatment with disease modifying antirheumatic drugs, such as methotrexate or synovectomy, is often beneficial [4]. However, the term post-Lyme disease symptoms or syndrome usually refers to subjective pain, neurocognitive, or fatigue symptoms that persist after antibiotic therapy. At one end of the spectrum, one or a few subjective symptoms such as malaise and fatigue or minor joint symptoms may persist for several months after antibiotic treatment of erythema migrans [6]. In a recent study, a subgroup of such patients had persistently high levels of interleukin 23, suggesting that hyperactive Th17 immune responses may have a role in their delayed recovery from the disease [7]. At the other end of the spectrum, and often after a gap of several months after treatment of the infection, patients may develop chronic, disabling joint and muscle pain, neurocognitive difficulties, and incapacitating fatigue that persist for years after antibiotic treatment for Lyme disease [8]. This chronic pain and fatigue syndrome may have different pathogenic mechanisms than those involved when symptoms resolve rather soon after antibiotic therapy. This chronic syndrome, which sometimes meets criteria for fibromyalgia or chronic fatigue syndrome, is not specific for Lyme disease [8]. Such symptoms may follow other infections or physical or emotional trauma, or the inciting cause may not be apparent. Moreover, using the serologic criteria of the Centers for Disease Control and Prevention [9],most patients with the diagnosis of “chronic Lyme disease” have little or no evidence of past or present B. burgdorferi infection [8]. Thus, in general usage, the term “chronic Lyme disease” has come to have a different and broader meaning than evidencebased descriptions of B. burgdorferi infection, and only a minority of patients with this diagnosis has evidence of preceding B. burgdorferi infection. Received 23 February 2014; accepted 25 February 2015; electronically published 6 April 2015. Correspondence: Allen C. Steere, MD, Massachusetts General Hospital, CNY 149/8301, 55 Fruit St, Boston, MA 02114 (asteere@mgh.harvard.edu). Clinical Infectious Diseases 2015;60(12):1783–5 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/civ187

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of North American (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists, and dermatologists in North America. It is important to realize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); should not be considered inclusive of all proper treatments methods of care, or as a statement of the standard of care; do not mandate any particular course of medical care; and are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Whether and the extent to which to follow guidelines is voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. Although IDSA, AAN, and ACR make every effort to present accurate, complete, and reliable information, these guidelines are presented “as is” without any warranty, either express or implied. IDSA, AAN, and ACR (and their officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented. The guidelines represent the proprietary and copyrighted property of IDSA, AAN, and ACR. Copyright 2020 Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology. All rights reserved. No part of these guidelines may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of IDSA, AAN, or ACR. Permission is granted to physicians and healthcare providers solely to copy and use the guidelines in their professional practices and clinical decision-making. No license or permission is granted to any person or entity, and prior written authorization by IDSA, AAN, or ACR is required, to sell, distribute, or modify the guidelines, or to make derivative works of or incorporate the guidelines into any product, including but not limited to clinical decision support software or any other software product. Except for the permission granted above, any person or entity desiring to use the guidelines in any way must contact IDSA, AAN, or ACR for approval in accordance with the terms and conditions of third party use, in particular any use of the guidelines in any software product. Summarized below are the 2020 recommendations for the prevention, diagnosis, and treatment of Lyme disease. The panel followed a systematic process used in the development of other Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) (see Figure 1). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text (http://onlinelibrary.wiley.com/doi/10.1002/acr.24495/abstract). A. Personal protective measures B. Repellents to prevent tick bites C. Removal of attached ticks A. Diagnostic tick testing B. Diagnostic testing of asymptomatic patients following tick bites Supplementary data. Supplementary materials (in addition to the full guideline) are available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24495/abstract. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Conflict of interest statement. See the Methodology section in the full guideline (on the Arthritis Care & Research website at http://online​library.wiley.com/doi/10.1002/acr.24495/abstract) for approach to conflict of interest (COI) by the IDSA/AAN/ACR COI review group. The following list is a reflection of what has been reported to the IDSA/AAN/ACR COI review group. To provide thorough transparency, the IDSA/AAN/ACR requires full disclosure of all relationships, regardless of relevancy to the guideline topic. The assessment of disclosed relationships for possible COI is based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. Dr. Lantos has received research funding from the National Cytomegalovirus Foundation and from the NIH and educational funding from Duke University; and has served as a consultant and reviewed trial protocol for Frederick O’Connor Medical Consultants, LLC. Dr. Bockenstedt has received research funding from the NIH and the Gordon and Llura Gund Foundation; has received remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research; and was awarded an endowed professorship as the Harold W. Jockers Professor of Medicine at Yale University. Dr. Falck-Ytter serves as director of the Evidence Foundation and the GRADE Network; conducts GRADE workshops with the Evidence Foundation; has served as the chair of the Guidelines Committee for the American Gastroenterological Association; and has received research funding from the Cleveland VA Medical Research and Education Foundation. Dr. Aguero-Rosenfeld serves as a council member for the New York City chapter of the American Society of Microbiology (ASM) and as a Board member of the American Lyme Disease Foundation; has provided legal testimony and consultation regarding Lyme disease and tick-borne diseases; and has received research grants from the NIH, BioFire, New York State Department of Health, and ViraMed. Dr. Auwaerter receives research funding from the Fisher Center for Environmental Infectious Diseases and the NIH; serves on the Board of Directors of the American Lyme Disease Foundation and as the Vice Chair of the Infectious Diseases Society of America (IDSA) Foundation; serves as a scientific advisor for DiaSorin, Adaptive Technologies, and Shionogi; provides legal expert opinion testimony regarding Lyme disease; had stock in Johnson & Johnson; has served as an editor for Johns Hopkins POC-IT ABX Guide, an advisor for the Food and Drug Administration (FDA), Genentech, Dynavax, Aradigm, Cempra, BioMérieux, Cerexa, and Medscape; has received research funding from Cerexa; has served on the FDA Advisory Board, the Medscape Advisory Board, and the IDSA Board of Directors; and his spouse has equity interest in venture capital–funded Capricor. Dr. Belani reviews non-continuing medical education (CME) lectures for and received honoraria and travel reimbursement from Horizon Therapeutics; and has received research funding from the NIH and the Children’s Hospitals and Clinics of Minnesota. Dr. Bowie has provided expert testimony to the Canadian Senate Subcommittee on Bill C-442: An Act Respecting a National Lyme Disease Strategy on behalf of the Association of Medical Microbiology and Infectious Disease Canada; and has received research funding from GlaxoSmithKline, Pfizer Canada, the Canadian Institutes of Health Research, and Vancouver Coastal Health Research Institute. Dr. Branda receives research funding from the Lyme Disease Biobank Foundation and Zeus Scientific; serves as a scientific advisor and consultant to DiaSorin, Inc.; has served as a scientific advisor and consultant for T2 Biosystems; has served on the scientific advisory board of Roche Diagnostics and AdvanDx; has received research funding from Karius, Inc., Alere, Inc., T2 Biosystems, BioMérieux, TBS Technologies, Immunetics, Inc., DiaSorin, Inc., Kephera Diagnostics, Inc., and the Bay Area Lyme Foundation; has participated in unfunded research collaborations with Karius Inc. and Kephera Diagnostics; was a member of the editorial board of the Journal of Clinical Microbiology; was a co-inventor on an application for a patent to protect intellectual property; and his spouse is an employee of Informed DNA. Dr. Clifford receives research funding from the NIH and the Alzheimer’s Association; serves as scientific consultant to Inhibikase and Excision BioTherapeutics; serves on Data and Safety Monitoring Boards (DSMB) for Biogen, Genzyme/Sanofi, Genentech, EMD Serono, Shire, Wave Life Sciences, Pfizer, Atara, Mitsubishi Tanabe, and IQVIA (formerly Quintiles); serves on Progressive Multifocal Leukoencephalopathy (PML) adjudication committees for Amgen, GlaxoSmithKline, EMD Serono, Bristol Myers Squibb, Roche, and the Takeda Oncology (formerly Millennium) Adjudication Committee–FDA, as well as Dr. Reddy’s Laboratories; has previously received research funding from the NIH; and his spouse formerly held stock in Johnson & Johnson. Dr. DiMario has received research funding from Novartis. Dr. Halperin serves as an Editorial Board Member of Neurology, and Vice Chair of the American Academy of Neurology (AAN) Guideline Subcommittee; has stock in Abbott Labs, AbbVie, Merck, and Johnson & Johnson; provides and has previously provided legal expert testimony defending physicians in medical malpractice cases on various neurologic issues, including Lyme disease; has received research funding from NIH, the Centers for Disease Control and Prevention (CDC); and has served as a section editor of neuroinfectious diseases in Neurology & Neuroscience Reports. Dr. Krause receives research funding from the Yale Emerging Infections Program; receives remuneration from Gold Standard Diagnostics for a collaborative research project; has stock in Gilead Sciences and First Trust NASDAQ Pharmaceuticals ETF; has received research funding from the NIH, the Centers for Disease Control and Prevention (CDC), the Gordon and Llura Gund Foundation, and L2 Diagnostics for NIH-sponsored research; has served as a scientific consultant and provided medical education and training for Oxford Immunotec, Inc.; has a patent pending (Enhanced Chemiluminescent enzyme-linked immunosorbent assay for detection of antibodies against Babesia microti), for which US Provisional Patent Application No. 62/580,588, was filed on November 2, 2017; serves on the Board of Directors for the American Lyme Disease Foundation and the Editorial Boards of Pathogens and Plos Neglected Tropical Diseases and the Editorial Advisory Board of Clinical Infectious Diseases; was on the Editorial Board of Journal of Clinical Microbiology, and will be on the Editorial Board of Clinical Microbiology Reviews starting January 2021. Dr. Liang has stock in Johnson & Johnson; received research funding from the Veterans Health Administration, the Arthritis Foundation, and the NIH; has served on the FDA Advisory Panel, Institute of Medicine panels; served as a scientific reviewer for the Research Grant Council of Hong Kong and the NIH; served on the Board of the Lupus Clinical Trials Consortium, Beacon Hill Villages, and Rx Foundation and advised the Institute for Clinical and Economic Review and the China Medical Board; previously had stock in Sequenom; and his spouse has stock in Johnson & Johnson. Dr. Meissner is a current member of the CDC Workgroups and serves as a volunteer consultant on the American Academy of Pediatrics Committee on Infectious Diseases and the NIH DSMB. Dr. Nigrovic receives research funding from the NIH, Department of Defense, and the NIH Center for Research Resources and for Advancing Translational Sciences (NCATS), Global Lyme Alliance, and Peabody Foundation; serves on the Editorial Board for Annals of Emergency Medicine; has served as scientific consultant for Adaptive Technologies; has received research funding from the NIH, Provider and Payer Quality Initiative (PPQI) Research Foundation, Harvard Catalyst, Hood Foundation, Bay Area Lyme Foundation, CDC, Emergency Medical Services for Children (EMSC), the National Patient-Centered Clinical Research Network (PCORNet), Milton Foundation, and Boston Children’s Hospital. Dr. Nocton receives research funding from Bristol Myers Squibb; serves as a member of the Subboard of Pediatric Rheumatology of the American Board of Pediatrics; and has received research funding from AbbVie, NIH, and the Arthritis Foundation. Dr. Pruitt has received research funding from Teva Pharmaceuticals and has served on the AAN Editorial Board of Neurology Clinical Practice. Ms Rips has received research funding from the Center for AIDS Research, Biogen Idec, Hoffmann-LaRoche, Sun Pharmaceutical Industries Ltd., Genzyme, the Alzheimer’s Association, and the American College of Radiology; and has served as a speaker for Teva Pharmaceuticals. Dr. Rosenfeld serves as a Council Member of the American College of Cardiology; has stock in Abbott, Proctor & Gamble, and General Electric; has received Fellowship Support from Boston Scientific, Medtronic, and Abbott Laboratories (formerly St. Jude Medical); has received research funding from Boehringer Ingelheim Pharmaceuticals, Inc.; and has served on the Program Committee and the Patient and Caregivers Committee of the Heart Rhythm Society. Dr. Savoy serves on the American Academy of Family Physicians (AAFP) Board of Directors, as an ex-officio Board member of Delaware Academy of Family Physicians (DAFP), as the Chair of the Centers for Medicare and Medicaid Services (CMS) Advisory Panel on Outreach and Education, and as Secretary of the Board of Directors of the Association of Departments of Family Medicine; receives honoraria from AAFP, DAFP, CMS, and Merck; has served on an Advisory Council for Highmark Health and as an advisor to the AAFP Adolescent Immunization Project; has received honoraria from AAFP; has served as the President of DAFP, as Editor of DelFamDoc, and as a member of AAFP Commissions. Dr. Sood has received research funding from the NIH; and has provided expert testimony for Danaher Lagnese, PC. Dr. Steere receives research funding from the NIH and the Mathers Foundation; has received research funding from the NIH, the American College of Rheumatology, the Mathers Foundation, the English-Bonter-Mitchell Foundation, Immunetics, Inc., Zeus Diagnostics, and the Ounsworth-Fitzgerald Foundation; and has served as a scientific advisor for Baxter Bioscience Institute of Systems Biology, Immunetics, Inc., Roche Diagnostics, and Viramed. Dr. Strle receives research funding from the Slovenian Research Agency; serves as the Head of Health Counsel of the Ministry of Health of the Republic of Slovenia and as a member of the Steering Committee for the European Society of Clinical Microbiology and Infectious Diseases Study Group for Lyme Borreliosis; serves on the Roche Diagnostics Advisory Board on Lyme Disease Diagnostics; and has received honoraria from Roche Diagnostics. Dr. Sundel receives research funding from the NIH and AbbVie, Inc.; serves as a content author and editor for UpToDate; provides expert testimony to Chin-Caplan, PC; has provided expert testimony for Conway Homer, PC; has served as an advisor for Paul Hastings, LLC; has served as a content editor for SimulConsult and as a Medical Education Resources lecturer for CME-granting educational courses; has received remuneration from SimulConsult as a co-investigator for an NIH-sponsored grant; and has received research funding from the NIH. Dr. Tsao receives research funding from the National Science Foundation, NIH, CDC, the Michigan Lyme Disease Association, and the Michigan Department of Health and Human Services; serves as a Scientific Council Advisor Member for the Canadian Lyme Disease Research Network and as a scientific advisor for the American Lyme Disease Association; has received research funding from Michigan State University; has served as an Associate Editor for Ticks and Tick-Borne Diseases and on the Tick Vectors, Surveillance, and Prevention Subcommittee of the US Department of Health and Human Services Tick-Borne Disease Working Group; and has received remuneration for providing educational seminars for Boehringer Ingelheim (formerly Merial). Dr. Wormser receives research funding from Immunetics, Inc., Rarecyte, Inc., Institute for Systems Biology, and Quidel Corporation; serves on the Board of the American Lyme Disease Foundation; provides and has previously provided expert testimony in malpractice cases; has stock in AbbVie, Inc. and Abbott Laboratories; has received research funding from the CDC, NIH, BioMérieux, Bio-Rad Laboratories, and DiaSorin, Inc; has served as a scientific research advisor for Baxter International and as a Lyme disease advisor and expert for the Missouri Board of Registration for the Healing Arts; has a patent approved (US patent no. 10,669,567 B2) for High Sensitivity Method for Early Lyme Disease Detection; filed 2 patent applications related to early Lyme disease detection (application no: 62/277,252) and Lyme arthritis and post-treatment Lyme disease syndrome (application no: 62/725,745); and has served on the Editorial Boards for Clinical Infectious Diseases, Vector-Borne and Zoonotic Diseases, and Ticks and Tick-Borne Diseases. Dr. Zemel has served as an advisor for Novartis Promotional Speakers Bureau. No other disclosures relevant to this article were reported. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. The expert panel expresses its gratitude for thoughtful reviews of an earlier version to the external reviewers. The panel thanks the IDSA, AAN, and ACR for supporting the guideline development process. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Lantos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Lyme disease caused by infection with a multitude of vector-borne organisms can sometimes be successfully treated in its very early stages. However, if diagnosis is delayed, this infection can become disseminated and, like another spirochetal infection syphilis, can affect multiple organ systems in the body, causing a wide variety of life-altering symptoms. Conventional antibiotic therapy may not be effective in eradicating the symptoms of the disease we know as Lyme disease. The recent literature has suggested that disulfiram (DSM) may be a potent drug in the armamentarium of physicians who treat chronic Lyme disease. The use of disulfiram in the treatment of Lyme disease started with a researcher who determined that DSM is bactericidal to spirochete. Encouraged by published case reports of apparent recovery from chronic Lyme disease, having prescribed DSM ourselves in the past for alcoholics who had a desire to stop drinking and prescribing it now for patients with chronic Lyme disease, we observed both predictable and potentially avoidable side effects not necessarily related to the ingestion of alcohol. We reviewed the published literature in PubMed and Google Scholar, using the following key words: Lyme Disease; Borrelia burgdorferi treatment; and disulfiram toxicity. This paper outlines the results of that research to help avoid some of the pitfalls inherent in this novel use of an old and established medication in the practice of clinical medicine.

Lyme Borreliosis

Unanswered questions in the management of patients with Lyme disease or those who have had Ixodes tick bites include: Is antimicrobial therapy effective in preventing Lyme disease during the incubation period of the infection? Which oral agents are most effective in treatment of Lyme disease? Are macrolides efficacious? And, for how long a time period should antimicrobial therapy be given? Potentially useful insights into these questions can be gained by examining experience with other spirochetal infections. Using this information, in conjunction with existing data from recent studies on Lyme borreliosis, tentative answers to these questions can be formulated. Based on this analysis, it would be anticipated that a short course of antibiotic therapy, perhaps even a single dose, will be effective in preventing Lyme disease after a tick bite. Beta-lactam antibiotics such as amoxicillin, and tetracycline preparations, such as doxycycline, are the mainstays of oral therapy for treatment of active infection. Macrolides are less effective, but their utility is likely to be improved if they are given in maximal dosage. There is no convincing evidence for extending treatment of early Lyme disease beyond 14 days. There is also no evidence that longer therapy is more efficacious for other manifestations of Lyme disease, although this issue deserves further study.

Dorsal Root Ganglion Stimulation for Post-Lyme Disease Chronic Peripheral Neuropathic Pain

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne illness in the United States. Many aspects of the disease are still topics of controversy within the scientific and medical communities. One particular point of debate is the etiology behind antibiotic treatment failure of a significant portion (10-30%) of Lyme disease patients. The condition in which patients with Lyme disease continue to experience a variety of symptoms months to years after the recommended antibiotic treatment is most recently referred to in the literature as post treatment Lyme disease syndrome (PTLDS) or just simply post treatment Lyme disease (PTLD). The most commonly proposed mechanisms behind treatment failure include host autoimmune responses, long-term sequelae from the initial Borrelia infection, and persistence of the spirochete. The aims of this review will focus on the in vitro, in vivo, and clinical evidence that either validates or challenges these mechanisms, particularly with regard to the role of the immune response in disease and resolution of the infection. Next generation treatments and research into identifying biomarkers to predict treatment responses and outcomes for Lyme disease patients are also discussed. It is essential that definitions and guidelines for Lyme disease evolve with the research to translate diagnostic and therapeutic advances to patient care.

Arthropod-borne diseases are a major problem whenever outdoor activities bring arthropods and people into contact. The arthropods discussed here include arachnids (ticks) and insects. Most arthropod bites and stings are minor, with the notable exception being bee-sting anaphylaxis. Ticks cause the most disease transmission. Key hard tick vectors include black-legged (Ixodes), dog (Dermacentor), and lone star (Amblyomma) ticks, which transmit Lyme and various rickettsial diseases. Insect repellents, permethrin sprays, and proper tick inspection reduce this risk significantly. Lyme disease and the milder southern-tick-associated rash illness (STARI) are characterized by the erythema migrans rash followed, in the case of Lyme disease, by early, disseminated, and late systemic symptoms. Treatment is with doxycycline or ceftriaxone. Indefinite treatment of "chronic Lyme disease" based on subjective symptoms is not beneficial. Rickettsial diseases include ehrlichiosis, anaplasmosis, and Rocky Mountain spotted fever, which are characterized by fever, headache, and possible rash and should be empirically treated with doxycycline while awaiting laboratory confirmation. Tularemia is a bacterial disease (Francisella) spread by ticks and rabbits and characterized by fever and adenopathy. Treatment is with gentamicin or streptomycin. Babesiosis is a protozoal disease, mimicking malaria, that causes a self-limited flu-like disease in healthy hosts but can be life threatening with immune compromise. Treatment is with atovaquone and azithromycin. Other tick-related conditions include viral diseases (Powassan, Colorado tick fever, heartland virus), tick-borne relapsing fever (Borrelia), and tick paralysis (toxin). Mosquitoes, lice, fleas, and mites are notable for their annoying bites but are increasingly significant disease vectors even in the United States.

There is no convincing evidence that classic Lyme disease occurs in Australia, nor is there evidence that the causative agent, Borrelia burgdorferi, is found in Australian animals or ticks. Lyme disease, however, can be acquired overseas but diagnosed in Australia; most people presenting with laboratory-confirmed Lyme disease in Australia were infected in Europe. Despite the lack of evidence that Lyme disease can be acquired in Australia, growing numbers of patients, their supporters, and some politicians demand diagnoses and treatment according to the protocols of the "chronic Lyme disease" school of thought. Antibiotic therapy for chronic "Lyme disease-like illness" can cause harm to both the individual (eg, cannula-related intravenous sepsis) and the broader community (increased antimicrobial resistance rates). Until there is strong evidence from well performed clinical studies that bacteria present in Australia cause a chronic debilitating illness that responds to prolonged antibiotics, treating patients with "Lyme disease-like illness" with prolonged antibiotic therapy is unjustified, and is likely to do much more harm than good.

Non-guideline-endorsed posttreatment courses of antibiotics for post-Lyme disease syndrome (PLDS) have been linked to adverse patient outcomes, but these findings have yet to be validated in large systematic evaluations. A retrospective cohort analysis of medical and pharmacy claims derived from the Truven Health Market Scan Commercial Claims and Encounters Database assessed 90-day incidence rates of adverse events (AEs) associated with PLDS treatment (PLDS-Tx). Patients were diagnosed with PLDS ≥6 months after initial diagnosis and standard antibiotic treatment for Lyme disease. Comparison cohorts included intravenous (IV) PLDS-Tx with or without oral antibiotics; oral antibiotic-only PLDS-Tx; or neither. Composite AE incidence rates were higher for patients treated with IV or oral PLDS-Tx than for patients not receiving either treatment (18.7%, 16.8%, and 13.4%, respectively; P = .019). Significant between-group differences in AE incidence rates were noted for electrolyte imbalance (4.0%, 1.5%, and 0.7%, respectively; P = .001) and infection (14.0%, 12.7%, and 9.3%; P = .006). Infection prevalence increased by 22.0% in the IV treatment group and 17.7% in the oral group. Incidence rates for all-cause and AE-related hospital stays and emergency department visits were higher for treated than nontreated patients, particularly when treatment was IV (all P < .01). Of IV-treated patients, 7.3% experienced an incident all-cause inpatient stay and 11.3% an incident all-cause emergency department visit, compared with, respectively, 2.2% and 3.4% of those treated with oral antibiotics and 0.9% and 1.9% of nontreated patients. Use of IV therapies or oral antibiotics for PLDS was associated with increased patient morbidity within 90 days.

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