Clinical Aspects of Lyme Disease Subcommittee Report to the Tick-Borne Disease Working Group

Disclaimer

Information and opinions in this report do not necessarily reflect the opinions of the Working Group, the U.S. Department of Health and Human Services, or any other component of the Federal Government. Readers should not consider the report or any part of it to be guidance or instruction regarding the diagnosis, care, or treatment of tick-borne diseases or to supersede in any way existing guidance. All subcommittee members actively participated in the development of this report. Members voted to approve submission of the report to the Working Group and on the wording of each of the possible actions contained in the report. The vote to submit the report indicates general agreement with the content of the document, but it does not necessarily indicate complete agreement with each and every statement in the full report.

Background and Goals

The Clinical Aspects of Lyme Disease Subcommittee’s primary focus is on the issues surrounding the diagnosis and treatment of persistent Lyme disease. Table 1 describes the group of experts assem-bled to address some of the major challenges presented by these issues.

Table 1: Members of the Clinical Aspects of Lyme Disease Subcommittee

Subcommittee Members	Type	Stakeholder Group	Expertise
(Co-chair) CDR Rebecca Bunnell, MPAS, PA-C, Senior Advisor, Learning and Diffusion Group, Innovation Center, Centers for Medicare & Medicaid Services, Baltimore, MD	Federal	Federal employee	Senior Advisor, Learning and Diffusion Group, Innovation Center, Centers for Medicare & Medicaid Services; health care provider
(Co-chair) Sam T. Donta, M, Infectious Disease Consultant, Falmouth Hospital, Falmouth, MA	Public	Health care provider	Basic science and clinical experience with Lyme disease; member of the Pathogenesis, Transmission, and Treatment Subcommittee of the first Tick-Borne Disease Working Group
John Aucott, MD, Director, Johns Hopkins Lyme Disease Research Center, Lutherville, MD	Public	Health care provider	Leading expert on biomarkers in patients previously treated for Lyme disease; served as chair of the first Tick-Borne Disease Working Group
Rex G. Carr, MD, Physician (specialty: physical medicine and rehabilitation), Hanover, NH (Resigned from subcommittee November 1)	Public	Academic researcher	Extensive clinical experience on the diagnosis and treatment of patients with persistent Lyme disease
Brian A. Fallon, MD, MPH, Professor of Clinical Psychiatry and Director of Lyme and Tick-Borne Diseases Research Center, Columbia University Irving Medical Center, New York, NY	Public	Academic research-er	Leading expert in clinical trials involving patients with persistent Lyme disease; author of seminal paper on neuropsychiatric manifestations of Lyme disease; served on the Pathogenesis, Transmission, and Treatment Subcommittee of the first Tick-Borne Disease Working Group
Katherine Murray Leisure, MD, Physician (specialty: infectious disease), Plymouth, MA	Public	Health care provider	Physician with expertise in emerging infections, research experience on the diagnosis and treatment of patients with leprosy and syphilis, and clinical experience in the treatment of patients with Lyme disease
Elizabeth Maloney, MD, Family Physician, President of Partnership for Tick-Borne Diseases Education, MN	Public	Health care provider	Experienced educator and reviewer of clinical research on Lyme disease; co-author of International Lyme and Associated Diseases Treatment Guidelines; served on the Pathogenesis, Transmission, and Treatment Subcommittee of the first Tick-Borne Disease Working Group
James K. Mingle, President and CEO, MyCareTeam, Chelmsford, MA	Public	Patient/advocate	Experience as successfully treated patient with Lyme disease; organizational and managerial skills

It is now known that the causative organism of Lyme disease, Borrelia burgdorferi, can persist in a number of animal models following infection and treatment with a “standard” course of antibiotics (Eisner, Hasley, Olsen, & Baumgarth, 2015; Embers et al., 2017; Hodzic, Feng, & Barthold, 2014; Straubinger, 2000). There are a few reports that this is the case in several patients as well (Häupl et al., 1993; Hudson et al., 1998; Marques et al., 2014; Oksi, Marjamaki, Nikoskelainen, & Viljanen, 1999; Pfister, Preac-Mursic, Wilske, Einhäupl, & Weinberger, 1989; Preac-Mursic et al., 1989; Preac-Mursic et al., 1993). The results of more recent studies in animal models by different investi-gators, including the nonhuman primate model, demonstrate that the persistent spirochetes are metabolically active and express bacterial genes, resulting in the expression of host genes months after initial infection and treatment (Greenmyer, Gaultney, Brissette, & Watt, 2018; Hodzic, Imai, & Escobar, 2019). These findings lend support to the probability that the effects of persisting organ-isms are a source, if not the likely source, of ongoing symptoms in patients who have unresolved Lyme disease. The pathophysiology of these ongoing symptoms remains to be defined, whether due to any direct effects of spirochete antigens on host functions, persisting antigens that result in immune or autoimmune reactions, a combination of both possibilities, or as-yet-to-be-discovered pathophysiologic events. These results then bring into sharper focus the importance of studying antibiotic treatment regimens differing from those used in previously conducted studies as a means of resolving the persisting infection.

The nomenclature that has been used to describe patients with ongoing symptoms has employed primarily two terms: chronic Lyme disease and post-treatment Lyme disease syndrome (PTLDS). Although a number of other infectious diseases and other diseases use “chronic” to describe ongo-ing illness, the use of “chronic” to describe patients who have ongoing symptoms attributable to Lyme disease has garnered an unfavorable reputation (Maloney, 2016). And the use of the term PTLDS implies to some that further use of antibiotic treatments is without benefit, for which sup-portive evidence is subject to a number of criticisms (as is later discussed in this report), and is like-ly an inappropriate term to describe patients with persistent symptoms who have received inade-quate treatment or no treatment at all. Recognizing that both terms—chronic Lyme disease and PTLDS—are likely to continue to be cited, this report uses the term “persistent Lyme disease” in conjunction with the basic science observations that the causative organisms can persist in both untreated and treated subjects. The term “persistent” does not speak to causation, be it due to continued B. burgdorferi infection, or to residual bacterial antigens to which there are inflammato-ry or other immune responses, or to as-yet-to-be-discovered pathophysiologic events, or to other bacterial or nonbacterial causes. An alternate suggested term might be “persistent symptoms” of Lyme disease, but this term could imply that there is no longer any infectious process, and there are no current means to determine whether this is or is not the case. Therefore, the term “persis-tent” itself is being used as the least inferential term in this report, with the knowledge that other terms may be preferred by some.

The primary goals of this subcommittee are to identify the gaps that exist in:

1. our understanding of the clinical picture of persistent Lyme disease and its symptoms and signs,
2. the use of current laboratory tests and other diagnostic modalities, and
3. the treatment of patients with persistent Lyme disease.

While similar questions exist in the evaluation of patients with earlier stages of Lyme disease, it is the persistent form that has created the greatest controversy regarding diagnosis and treatment. To that end, the subcommittee has addressed these issues, with resultant recommendations for po-tential actions that should lead to improvements in the current status pertaining to the diagnosis and treatment of patients with persistent Lyme disease, and, ultimately, in improved patient care.

Methods

The subcommittee consisted of eight members, including one Federal partner, representing public health, academia/research, patients, and clinical practice. Co-chair Sam Donta, MD, was selected as a member of the Tick-Borne Disease Working Group and as co-chair of this subcommittee based on his extensive clinical and basic science background in Lyme disease. The other subcommittee members were selected for their clinical and research experience with Lyme disease. One sub-committee member was a successfully treated patient with persistent Lyme disease. (One sub-committee member resigned on November 1.) Members’ areas of expertise are described in Table 1.

The subcommittee met 13 times from July 17 through December 18, 2020. At the first meeting, the subcommittee co-chairs circulated several proposed topics, which were then discussed. Also discussed was the process by which the subcommittee would propose potential actions and how those suggestions would be presented to the Working Group. Through ongoing discussion, mem-bers proposed topics and potential presenters, including presentations from subcommittee mem-bers themselves, as well as from other leading experts in the field. Meetings consisted of brief presentations from members or invited guests on topics of interest, followed by discussion with the presenter and follow-up discussion among the members only. Table 2 gives an overview of the subcommittee’s meetings; Table 3 summarizes the presentations at each meeting. Appendix 1 pro-vides the agenda and a brief of each meeting.

Subcommittee co-chairs drafted segments of the report and circulated them for review by the sub-committee. Members submitted comments by email and discussed the draft report briefly during meetings. The co-chairs revised the drafts according to the consensus of the group. At the final meeting, members voted on each section of the report and each proposed potential action (see Table 4). (Subcommittee members who were unable to attend the final meeting submitted their votes by email.)

Table 2: Overview of the Clinical Aspects of Lyme Disease Subcommittee Meetings

Meeting No.	Data	Present	Topics Addressed
1	July 17, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair John Aucott, MD Rex G. Carr, MD Katherine Murray Lei-sure, MD Elizabeth Maloney, MD James K. Mingle	Introductions; purpose of the subcommittee; timeline for report development; topics to address in report; potential guest speakers; agenda for next meeting.
2	July 31, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair John Aucott, MD Rex G. Carr, MD Katherine Murray Lei-sure, MD Elizabeth Maloney, MD James K. Mingle	Presentation from Marianne J. Middelveen, MS, on evidence of sexual transmission of Borrelia burgdorferi; potential presenters for upcoming meetings.
3	August 14, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair John Aucott, MD Rex G. Carr, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Inclusion in subcommittee report of sexual transmission of B. burgdorferi as a low-priority topic for further research; presentation from member Sam Donta, MD, on issues in the clinical diagnosis of persistent Lyme disease; suggestions for future guest speakers.
4	August 28, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair Rex G. Carr, MD Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Presentation from Steven Schutzer, MD, on cerebrospinal fluid prote-omics and potential biomarker discovery for persistent Lyme disease; potential presenters for upcoming meetings.
5	September 11, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair John Aucott, MD Rex G. Carr, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Presentation from member John Aucott, MD, on current, cutting-edge, and potential diagnostic tests for Lyme disease; review of slide presentation on subcommittee background and methods for the Tick-Borne Disease Working Group meeting on September 12
6	September 25, 2019	Sam T. Donta, MD, Co-Chair Rex G. Carr, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Presentation from member Sam Donta, MD, on issues in the treatment of persistent Lyme disease; discussion of gaps in understanding around the diagnosis and treatment of persistent Lyme disease.
7	October 9, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair Rex G. Carr, MD Brian A. Fallon, MD, MPH Elizabeth Maloney, MD James K. Mingle	Presentation from member Rex Carr, MD, on the successful use of antibiotics to treat persistent Lyme disease and potential mechanisms of action; review of upcoming meetings and report development.
8	October 16, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair Brian A. Fallon, MD, MPH Elizabeth Maloney, MD James K. Mingle	Presentation from Ying Zhang, MD, PhD, on the potential utility of certain combinations of antibiotics in vitro and in vivo, modeling the experience with tuberculosis; review of upcoming meetings and report development.
9	November 6, 2019	Sam T. Donta, MD, Co-Chair John Aucott, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Presentation from members John Aucott, MD, Sam Donta, MD, and Brian Fallon, MD, about their experiences with the utility and findings of brain imaging in people with Lyme disease; review of upcoming meetings and report development.
10	November 13, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair John Aucott, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Presentation from member Elizabeth Maloney, MD, on maternal-fetal transmission of Lyme disease; review of upcoming meetings and report development.
11	November 20, 2019	Sam T. Donta, MD, Co-Chair John Aucott, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Open discussion with Paul Auwaerter, MBA, MD, past president of the Infectious Diseases Society of America, about policies and practices in the diagnosis and treatment of Lyme disease; review of upcoming meetings and report development.
12	December 4, 2019	CDR Rebecca Bunnell, MPAS, PA-C, Co-Chair Sam T. Donta, MD, Co-Chair John Aucott, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD James K. Mingle	Review of subcommittee report to the Tick-Borne Disease Working Group; review of upcoming meetings.
13	December 18, 2019	Sam T. Donta, MD, Co-Chair John Aucott, MD Brian A. Fallon, MD, MPH Katherine Murray Leisure, MD Elizabeth Maloney, MD	Review of subcommittee report to the Tick-Borne Disease Working Group and voting.

In addressing patients with persistent Lyme disease, the subcommittee heard from subcommittee members as well as from outside speakers (see Table 3).

Table 3: Presenters to the Clinical Aspects of Lyme Disease Subcommittee

Meeting No.	Presenter	Topics Addressed	Ok to Share?
1	None	n/a	n/a
2	Marianne J. Middelveen, MS, Researcher, Atkins Veterinary Services of Calgary	Evidence of sexual transmission of Borrelia burgdorferi	No
3	Sam Donta, MD, Infectious Disease Consultant, Falmouth Hospital	Issues in the clinical diagnosis of persistent Lyme disease	Yes
4	Steven Schutzer, MD, Professor, Rutgers, New Jersey Medical School, Medicine, Division of Allergy and Immunology	Cerebrospinal fluid proteomics and potential biomarker discovery for persistent Lyme disease	Yes
5	John Aucott, MD, Director, Johns Hopkins Lyme Disease Research Center	Current, cutting-edge, and potential diagnostic tests for Lyme disease	Yes
6	Sam Donta, MD, Infectious Disease Consultant, Falmouth Hospital	Issues in the treatment of persistent Lyme disease; gaps surrounding the diagnosis and treatment of persistent Lyme disease	Yes
7	Rex G. Carr, MD, Physician (specialty: physical medicine and rehabilitation)	Successful use of antibiotics to treat persistent Lyme disease and potential mechanisms of action	Yes
8	Ying Zhang, MD, PhD, Professor, Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins Univer-sity	Effectiveness of treating persistent Lyme disease with combination drug therapies that include antibiotics, essential oils, or herbal products that target the persisters of B. burgdorferi	No
9	John Aucott, MD, Director, Johns Hopkins Lyme Disease Research Center	Use of a novel imaging approach to assess inflammation in the brain of people with Lyme disease	No
9	Sam Donta, MD, Infectious Disease Consultant, Falmouth Hospital	Findings from single-photon emission computed tomography (SPECT) imaging of patients with serologic evidence of Lyme infection before and after treatment	Yes
9	Brian A. Fallon, MD, MPH, Professor of Clinical Psychiatry and Director of Lyme and Tick-Borne Diseases Research Center, Columbia University Irving Medical Center	Review of findings from brain imaging studies of in people with Lyme encephalopathy	No
10	Elizabeth Maloney, MD, Family Physician and President of Partnership for Tick-Borne Diseases Education	Gestational and congenital Lyme disease and the need to educate the public and health care providers about the risk of Lyme disease in pregnancy	Yes
11	Paul Auwaerter, MBA, MD, Clinical Director, Division of Infectious Diseases, Professor of Medicine, Johns Hopkins University; Past President (2018), Infectious Diseases Society of America	Policies and practices in the diagnosis and treatment of Lyme disease, particularly for people who continue to have symptoms long after the infection (whether treated or untreated)	No

Table 4: Votes Taken by the Clinical Aspects of Lyme Disease Subcommittee

Meeting No.	Motion	Results	Minority
13	Approval of Background section	Motion passed 6 in favor, 0 opposed, 0 abstained, 1 absent	No
13	Approval of Methods section, pending possible elaboration on how the report was drafted and how decisions were made	Motion passed 6 in favor, 0 opposed, 0 abstained, 1 absent	No
13	Approval of Priority 1	Motion passed 6 in favor, 0 opposed, 0 abstained, 1 absent	No
13	Approval of Priority 2	Motion passed 6 in favor, 0 opposed, 0 abstained, 1 absent	No
13	Approval of Priority 3	Motion passed 5 in favor, 1 opposed, 0 abstained, 1 absent	No
13	Approval of Priority 4	Motion passed 6 in favor, 0 opposed, 0 abstained, 1 absent	No

Results and Potential Actions

For consideration by the Tick-Borne Disease Working Group, the Clinical Aspects of Lyme Disease Subcommittee has identified four major priorities and six potential actions to achieve them.

Priority 1: Conduct additional targeted controlled clinical treatment trials in patients with early and persistent Lyme disease, using different antibiotic regimens and longer durations of treatment than those used in previously conducted trials.

Assessment of the clinical presentation of patients with persistent Lyme disease involves a fre-quently complicated differential diagnosis that includes chronic fatigue syndrome and fibromyalgia, among other multi-symptom infectious and noninfectious diseases and disorders (Donta, 2002). Complicating support of the clinical diagnosis of persistent Lyme disease is the limited value of ex-isting laboratory tests, mostly serologic tests, which offer indirect evidence of exposure to B. burgdorferi. Other, more direct tests (for example, PCR-DNA, culture) appear to be insufficiently sensitive, either because the remaining organisms are not in the traditional sites sampled for analy-sis, or because the bacterial load is too low to be detectable, or both. Therefore, a high priority to address this obvious gap in critical information is the development of direct detection tests, if that goal is possible to achieve, or other better indicators of ongoing infection or alternative causes of the persistent disease.

In reviewing the available laboratory tests, the subcommittee noted that tests such as enzyme-linked immunosorbent assays (ELISAs) are insensitive and frequently negative in patients with per-sistent Lyme disease. The reasons for this are unclear but may have to do with a more muted im-munologic response in some patients with this form of Lyme disease. In contrast to patients with Lyme arthritis, who have robust immunoglobulin (Ig) G responses to B. burgdorferi and seem to do well with a limited course of antibiotic treatment, patients with persistent Lyme disease frequent-ly have limited IgG responses to B. burgdorferi antigens when tested by western blot (Donta, 2012), results perhaps indicating an inadequate or ineffective host immune response to the infec-tion. In support of this conjecture, studies in animal models demonstrate that B. burgdorferi inter-feres with the development of normal IgM/IgG transitional responses and with other innate im-mune system responses (Eisner et al., 2015). Furthermore, as with findings in animal models (Eisner et al., 2015; Embers et al., 2017; Hodzic et al., 2014), such patients frequently exhibit continued IgM reactivity to specific B. burgdorferi antigens, for example, 23kd (outer surface protein [Osp] C) and 39kd, in addition to the less specific flagellar 41kd protein, results in line with an inability of the host to adequately clear the infection (Donta, 2012).

To further complicate the use of these serologic tests to affirm or refute the diagnosis of Lyme dis-ease, the more stringent criteria that were developed by the Centers for Disease Control and Pre-vention (CDC) for surveillance purposes were adopted de facto for general clinical use, with the unfortunate result of patients being told they did not have Lyme disease if they did not have the appropriate number of IgG responses. Based on the CDC surveillance criteria, there must be at least five IgG responses, but there has been no study in patients with persistent Lyme disease to support those surveillance criteria being adopted for clinical use.

The other issue is the interpretation that any IgM reactivity in patients with persistent Lyme dis-ease is to be considered a false-positive, and this cautionary statement is included in the reports of several commercial laboratories. Without more evidence to support this interpretation, and with the accumulated evidence of persistent IgM responses in animals with persisting organisms, it is more likely that the IgM responses frequently seen in such patients are compatible with ongoing infection. There is clinical support for this latter interpretation, as is discussed later in this report. Based on the aforementioned data, educational efforts to correct this misunderstanding should help clinicians improve their assessment and management of patients with potential persistent Lyme disease. The gaps that exist here are that there are no existing direct detection tests to as-sess the presence or absence of active B. burgdorferi infection in patients with persistent Lyme disease and that the use of current serologic-based tests are of limited value in assisting the clini-cian to make a diagnosis of persistent Lyme disease.

Proteins unique to patients with PTLDS have been found in cerebrospinal fluid, as compared with patients with chronic fatigue syndrome and healthy patients (Schutzer et al., 2011). In addition, proteins unique to patients with multiple sclerosis have been identified, as compared with pa-tients with other neurologic disorders and healthy patients (Schutzer et al., 2013). These unique proteins have yet to be defined and likely represent host response proteins to the specific illness-es. Whether further analyses of these proteins would reveal more specific biomarkers that would be helpful in the clinical diagnosis of persistent Lyme disease is a potential action item to pursue.

Other host biomarkers have been identified in patients who were seen initially with erythema mi-grans as their presenting symptom of Lyme disease, were treated with a standard course of doxycy-cline, and continued to have symptoms. In these patients, levels of CCL19 and interleukin 23 re-mained elevated (Aucott et al., 2016). There were also small-molecule metabolomic signatures in patients with persistent disease (Bouquet et al., 2016). Whether use of these or other biomarkers would improve the clinical diagnosis and care of patients with persistent disease is another poten-tial action item.

Another item of interest and discussion was the adjunctive use of radiotracer imaging of the brain as both a diagnostic tool and as a monitoring tool in patients with persistent Lyme disease. Studies using single-photon emission computed tomography (SPECT), positron emission tomography (PET), and novel ligands demonstrate abnormalities in metabolic activity, blood flow, and glial cell activity in the brains of patients with persistent Lyme disease (Coughlin et al., 2018; Donta, Noto, & Vento, 2012; Fallon, Keilp, Prohovnik, Heertum, & Mann, 2003; Fallon et al., 2009). It would seem that the decreased metabolic activity in such patients would be responsible for altered blood flow and for neurocognitive dysfunction in these patients. Of note, use of certain antibiotic regimens led to reversal of these defects (Donta et al., 2012; Logigian et al., 1997). Whether the use of any of these imaging modalities would improve the diagnosis and treatment of persistent Lyme disease is a con-tinuing subject of discussion.

The subcommittee reviewed the results of prior published controlled studies of antibiotic treat-ment (DeLong, Blossom, Maloney, & Phillips, 2012; Klempner et al., 2013). As review of those stud-ies was included in the previous report of the Working Group, details of that discussion are not re-peated here. The subcommittee members noted shortcomings in those studies, including the types of antibiotics used, the numbers of patients, the duration of treatment, and interpretation of out-come results.

The subcommittee also reviewed published observational studies of alternative antibiotic treat-ment regimens. Tetracycline has reportedly been used successfully in treating patients with persis-tent illness (Donta, 1997), as has the combination of a macrolide antibiotic (for example, clarithro-mycin, azithromycin, or erythromycin) and a lysosomotropic agent (for example, hydroxychloro-quine or amantadine) (Donta, 2003). The rationale for the use of tetracycline instead of doxycycline (or minocycline) is based on a more favorable pharmacokinetic profile for tetracycline, including much less protein binding, and higher amounts of tetracycline (1,500 mg/day vs. 200 mg/day of doxycycline) used for treatment. Successful treatment, defined as apparent cure or sustained levels of improvement months to years after cessation of antibiotic treatment, was dependent on the severity of patient symptoms, duration of illness, and duration of antibiotic treatment. Treatment success was greatest in patients with shorter durations of illness and treatments, averaging 3–6 months in patients with illness less than a year, or 12–18 months in patients with durations of ill-ness greater than 3 years. It was also noted that IgM reactivity resolved, along with increased IgG activity, in successfully treated patients (Donta, 1997), results consistent with the aforementioned inadequate host response that has apparently benefited by the use of a specific antibiotic regimen to help resolve the apparent infection.

Similar results were noted with the macrolide/lysosomotropic regimen. It had been previously noted in the literature that treatment with a macrolide antibiotic alone, despite its excellent in vitro activity against B. burgdorferi and excellent tissue and intracellular concentrations, was asso-ciated with treatment failure (Donta 2003; Luft, Gorevic, Halperin, Volkman, & Dattwyler, 1989). This apparent paradox appears to be due to the macrolide’s limited activity in an acidic milieu. If persisting B. burgdorferi exist in an intracellular endosome that is rendered acidic by the organism itself, as is the case described with a number of other organisms capable of persistence (Donta, 2003), then a macrolide antibiotic would be relatively ineffective in such a milieu. Based on this hypothesis, and on the findings of enhanced antibiotic killing of Coxiella burnetii in a tissue culture model of infection in the presence of an alkalinizing agent (Maurin, Benoliel, Bongrand, & Raoult, 1992), it was found that the adjunctive use of hydroxychloroquine resolved persistent Lyme dis-ease (Donta, 2003). Use of hydroxychloroquine alone in such patients was without therapeutic ef-fect. In further support of that hypothesis, the adjunctive use of hydroxychloroquine with tetracy-cline, which is active in an acidic milieu, was without additional benefit. And as with observations with the tetracycline regimen, duration of illness and treatment were key factors in achieving suc-cessful outcomes (Donta, 2003). Despite these published clinical observations, without controlled treatment trials to validate these observations, there can remain skepticism about the efficacy of either or both of these treatment regimens, and of other anecdotal observations as well (Horowitz & Freeman, 2019; Liegner, 2019). If and until controlled clinical trials of various apparently success-ful antibiotic regimens in patients selected according to duration of illness and design of patient-acceptable treatment trials of longer durations than those previously conducted are possible, health care providers may have to exercise their clinical judgment as to how best diagnose and treat patients with persistent Lyme disease.

Further clinical observations relate to the potential importance of the type of antibiotic used for treatment. In some cases, certain generic versions of an antibiotic are more effective and better tolerated than the brand version (Dunne, Shannon, Dunne, & Cullen, 2013; Galleli et al., 2013). Patients frequently experience an intensification of symptoms upon initiation of specific antibiotic treatment, often referred to as Jarisch-Herxheimer reactions, and symptom fluctuations during the course of treatment, findings which could otherwise be misinterpreted as failure of treatment. Such patients have generally increased host immune and other host responses in an attempt to clear the infection; anti-immune therapy might temporarily appear to be effective, but ultimately it is ineffective without further antibiotic treatment and might be detrimental in terms of duration of illness and response to the antibiotic regimen.

As a result of further discussion of the role of certain antibiotic regimens in the treatment of pa-tients with persistent Lyme disease, it is apparent that a gap continues to exist between the pub-lished controlled treatment studies and the published and unpublished clinical observations re-garding this issue. Potential actions could include the use of additional targeted clinical trials em-ploying different antibiotic regimens, such as those described above and those currently in devel-opment or in the discovery phase. If the results of those trials demonstrate the effectiveness of the particular treatment regimen, adoption of that treatment regimen would then result in improved patient care, along with the additional benefits of reduced patient morbidity and associated health care costs.

One of the potential explanations for the apparent failure of certain antibiotic regimens, in particu-lar shorter-duration treatment regimens, is the presence of antibiotic-tolerant persisting organisms. Recent literature has described the presence of such organisms, including in vitro and in vivo data on persisting B. burgdorferi and the effectiveness of certain antibiotics, some in combination, on curing the persistent state (Sharma, Brown, Matluck, Hu, & Lewis, 2015). There is also evidence from recent studies of persisting B. burgdorferi in vitro and in mouse models, that certain other antibiotics, especially some in combination, and other non-antibiotic compounds, are more effec-tive against these persisters than currently used antibiotic regimens (Feng et al., 2018; Feng et al., 2019). Potential actionable recommendations, then, would be to conduct initial clinical trials in patients with PTLDS or in treatment-naïve patients, using clinically acceptable combination antibi-otic treatments and, perhaps, some non-antibiotic regimens.

Possible Opportunities

Based on accumulating evidence from the results of studies in animal models, it appears likely that the continuing symptoms in some patients who have or have not been previously treated with cer-tain antibiotic regimens are due to persisting, metabolically active B. burgdorferi. Recognizing some of the shortfalls of previously conducted controlled antibiotic treatment trials, along with recognition that persistent B. burgdorferi are capable of altering and evading host immune re-sponses and capable of forming persister cells following certain antibiotic treatments, there is the real possibility and opportunity to utilize other antibiotic regimens to prevent the formation of persistent B. burgdorferi, as well as to successfully treat patients with persistent Lyme disease. To-ward that end, the subcommittee discussed two potential actions, which are proposed to the Working Group.

Threats or Challenges

Potentially hampering the conduct of additional controlled antibiotic treatment trials are several factors, such as the lack of a B. burgdorferi-specific antigen detection test or other relatively specif-ic biomarker to document the continuing presence or absence of the organism; potential difficul-ties in recruitment of a homogeneous group of patients as regards to duration of illness, severity of illness, and serologic status; and whether trials of longer duration would include true placebo groups or would compare differing antibiotic and non-antibiotic regimens. Notwithstanding these challenges, it should be possible to conduct targeted treatment trials, the results of which could have a major impact on care of such patients.

Priority 1 Potential Actions

Potential Action 1.1:

Establish a clinical treatment trials network to evaluate the potential of vari-ous antibiotic and non-antibiotic treatment regimens in patients with persistent Lyme disease. This clinical trials network would participate in studies that include the use of antibiotic regimens dif-fering from those used in previously conducted studies and of longer durations in patients with persistent Lyme disease. A planning committee including involved stakeholders (clinicians and re-searchers representing a range of scientific and medical perspectives, patient advocates, and gov-ernment funding agencies) should be established to discuss the essential components of future clinical trials. Experts in clinical trial design and biostatistics should be included on the planning committee as well to ensure the integrity of patient inclusion criteria, study design, selection of outcome measures, and methods used to analyze the results of the trials. Patient inclusion criteria could include the following: a) patients previously treated to some extent (patients with PTLDS); b) patients with persisting symptoms who were not previously treated; and c) patients with less strin-gent serologic evidence of exposure to B. burgdorferi. A particularly more homogeneous and im-portant group of patients to be studied would be those with early Lyme disease, using longer courses of treatment, a combination of antibiotics, or both, to determine whether the results of these studies would lead to a lower incidence of subsequent persistent Lyme disease. With the establishment of a clinical treatment trials network and planning committee as described, it is like-ly that the eventual results of these clinical trials would be generally acceptable and have a broad impact on the future management of patients with Lyme disease.

Vote on Potential Action 1.1

Number in Favor	Number Opposed	Number Abstained	Number Absent
6	0	0	1

Potential Action 1.2:

Target research funding for the development of specific detection tests or biomarkers to determine whether persistent Lyme disease is due to continuing infection by B. burgdorferi and to monitor the results of treatment.

Vote on Potential Action 1.2

Number in Favor	Number Opposed	Number Abstained	Number Absent
6	0	0	1

Priority 2: Educate clinicians as to the limitations of currently available tests in the diagnosis and in the monitoring of treatment of patients with persistent Lyme disease.

There is a disparity between and among societal and government agencies and clinicians as to rec-ommendations regarding the use of existing tests in the diagnosis of persistent Lyme disease and of its treatment (Donta, 2012). In discussing potential actions to resolve these problems, there is a need to consider whether additional controlled treatment trials are feasible, given the absence of specific corroborative tests, the challenge of identifying sufficiently homogeneous clinical popula-tions, and the lack of consensus about the best antibiotic regimens to be tested. If and until re-search results are sufficiently conclusive to support recommendation of a specific regimen for gen-eral use, as part of educational efforts, health care providers should consider the use of currently available, apparently successful, treatment regimens, as previously noted.

Possible Opportunities

There is now updated information from the results of animal studies that the causative agent of Lyme disease, B. burgdorferi, can often resist innate and other host immune responses and can persist despite certain antibiotic treatments. Educating clinicians about these important results, along with information regarding the limitation of existing laboratory tests and of the limitations of previously conducted antibiotic treatment trials, should enable them to better manage and care for patients with persistent Lyme disease.

Threats or Challenges

The greatest challenge to changing current stated recommendations by some organizations and in-dividuals regarding the utility of existing serologic tests in the diagnosis of patients with persistent Lyme disease, and of the shortcomings of the results of antibiotic treatment trials conducted thus far, is whether the recommendations of these individuals and organizations are so entrenched that they are willing to change their recommendations. It is hoped that, in light of accumulating infor-mation regarding the likelihood that persistent Lyme disease is due to continuing active B. burgdorferi infection, there will be a consensus that further research is needed to find better means to assist health care providers in their management of patients with persistent Lyme dis-ease.

The subcommittee discussed two potential actions, which are proposed to the Working Group.

Priority 2 Potential Actions

Potential Action 2.1:

CDC should develop educational modules on limitations of available testing in the diagnosis and in the monitoring of treatment of persistent Lyme disease and of the limitations in the interpretations of the results of previously conducted controlled antibiotic treatment trials.

Vote on Potential Action 2.1

Number in Favor	Number Opposed	Number Abstained	Number Absent
6	0	0	1

Potential Action 2.2:

Provide Federal and state support for the use of regional and local clinician forums to educate clinicians as to the limitations of available testing in the diagnosis and in the monitoring of treatment of persistent Lyme disease and of the limitations in the interpretations of the results of previously conducted controlled antibiotic treatment trials.

Vote on Potential Action 2.2

Number in Favor	Number Opposed	Number Abstained	Number Absent
6	0	0	1

Priority 3: Further evaluate purported human-to-human sexual transmission of Lyme disease.

The subcommittee also considered findings related to the potential sexual transmission of Lyme disease (Stricker & Middelveen, 2015). The subcommittee concluded that there was limited evi-dence to support sexual transmission of Lyme disease, given the lack of epidemiological evidence and the seasonality of Lyme disease, among other factors, along with concerns by some subcommit-tee members regarding the methodology used to support the findings. But because of the implica-tions of sexual transmission, some members recommended that further studies be conducted to validate or refute this possible mode of transmission, the potential action being of lower priority.

Possible Opportunities

Additional research should be able to provide evidence in support of or against the proposition that Lyme disease might be sexually transmitted in some cases.

Threats or Challenges

Despite the preponderance of evidence against the proposition that Lyme disease can be sexually transmitted, unless further controlled studies are conducted to refute or support the supposition that Lyme disease could be sexually transmitted, this possibility will continue to be espoused by some. Therefore, the subcommittee discussed a potential action, which is proposed to the Working Group.

Priority 3 Potential Action

Potential Action 3.1:

Provide funding for research to support or refute the purported human-to-human sexual transmission of Lyme disease.

Vote on Potential Action 3.1

Number in Favor	Number Opposed	Number Abstained	Number Absent
3	3	0	1

Priority 4: Further evaluate potential maternal-fetal transmission of Lyme disease and of congenital Lyme disease.

The subcommittee considered the role of maternal-fetal transmission of Lyme disease. There is lim-ited evidence linking gestational Lyme disease to adverse pregnancy outcomes (Gardner, 2001; Lakos & Solymosi, 2010; Waddell Greig, Lindsay, Hinckley, & Ogden, 2018; Walsh, Mayer, & Baxi, 2007). While it appears that the prognosis for the fetus is favorable when gestational Lyme disease is promptly diagnosed and treated with appropriate antibiotics, untreated gestational disease is associated with a higher rate of adverse pregnancy outcomes (Lakos & Solymosi, 2010; Waddell et al., 2018). Although a broad spectrum of adverse fetal outcomes has been noted, a congenital syn-drome has not been identified (Gardner, 2001; Walsh et al., 2007).

Possible Opportunities

Additional studies of the incidence of potential maternal-fetal transmission of B. burgdorferi should provide information to help answer frequently asked questions and assumptions about this mode of transmission. Similarly, additional studies of potential congenital Lyme disease, and of persistent Lyme disease in infants resulting from maternal transmission of B. burgdorferi, would help answer this question as well. A registry including a number of institutions should help answer these ques-tions.

Threats or Challenges

Without additional studies of the extent to which maternal-fetal transmission of B. burgdorferi oc-curs, the consequences thereof, and the extent to which there is any congenital Lyme disease or any transmissible, persistent Lyme disease in infants, there will be uncertainty and angst for preg-nant women, their families, and clinicians regarding these possible modes of transmission. There-fore, the subcommittee discussed a potential action, which is proposed to the Working Group.

Priority 4 Potential Action

Potential Action 4.1:

Provide funding for a registry and more studies to determine the extent of maternal-fetal transmission of Lyme disease and of any congenital Lyme disease.

Vote on Potential Action 4.1

Number in Favor	Number Opposed	Number Abstained	Number Absent
6	0	0	1

Summary

The Clinical Aspects of Lyme Disease Subcommittee tackled the difficult issues surrounding the di-agnosis and treatment of persistent Lyme disease. Based on a review of updated information re-garding the pathogenesis and pathophysiology of the ability of the causative agent of Lyme disease, B. burgdorferi, to persist and be active in animal models, along with the reports that B. burgdorferi was recovered in a number of human cases as well, it is likely that it is continuing active infection that is responsible for the continuing symptoms and signs in patients with persistent Lyme disease. Although the mechanisms underlying the pathophysiology of persistent illness remain to be de-fined, the opportunity exists—through the conduct of targeted controlled antibiotic, and perhaps non-antibiotic, treatment trials, in patients with persistent illness, using regimens from both the results of animal studies and observational studies in humans—that better treatment regimens can be found to improve and, it is hoped, resolve the persistent disease.

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Appendix 1: Clinical Aspects of Lyme Disease Subcommittee Agendas and Brief Meeting Overview

Meeting 1, July 17, 2019

Agenda

1. Introductions of each subcommittee member
2. Why subcommittee exists—what to accomplish
   1. Review the milestones
   2. Review the topics suggested for the subcommittee report
   3. Discuss additional topics
   4. Discuss potential guest speakers

Overview

The subcommittee members discussed the purpose and goals of the subcommittee.

Meeting 2, July 31, 2019

Agenda

1. Roll call
2. Presentation: Borrelia burgdorferi: Evidence of sexual transmission
3. Discussion
4. Topics for upcoming meetings

Overview

The subcommittee members heard a presentation on the evidence of sexual transmission of B. burgdorferi and discussed the implications of the findings.

Meeting 3, August 14, 2019

Agenda

1. Roll call
2. Discussion of previous meeting presentation
3. Presentation: Issues in the clinical diagnosis of persistent Lyme disease
4. Discussion
5. Upcoming meetings

Overview

The subcommittee members heard a presentation on issues in the clinical diagnosis of persistent Lyme disease and discussed the implications.

Meeting 4, August 28, 2019

Agenda

1. Roll call
2. Presentation: Steven Schutzer, MD: Research on proteomics and potential biomarkers discovery for persistent Lyme Disease, chronic fatigue syndrome, multiple sclerosis patients, and healthy controls
3. Plans for next meeting

Overview

Steven Schutzer, MD, reviewed his work at Rutgers investigating the proteomics of cerebral spinal fluid in healthy individuals compared with patients with persistent Lyme disease, chronic fatigue syndrome, or multiple sclerosis in order to identify potential disease biomarkers, and the subcommittee members discussed the implications of the research.

Meeting 5, September 11, 2019

Agenda

1. Roll call
2. Presentation: John Aucott: Current and potential laboratory tests and biomarkers for persistent Lyme disease
3. Slide deck for Working Group meeting
4. Upcoming meetings

Overview

The subcommittee heard a presentation from member John Aucott, MD, who reviewed current and cutting-edge diagnostic tests for Lyme disease, and discussed the implications of the research.

Meeting 6, September 25, 2019

Agenda

1. Roll call
2. Discussion: Gaps in diagnosis
3. Presentation: Sam Donta: Treatment of persistent Lyme disease
4. Upcoming meetings

Overview

The subcommittee heard a presentation from member Sam Donta, MD, who reviewed issues in the treatment of persistent Lyme disease, and discussed gaps in understanding around diagnosis and treatment of persistent Lyme disease.

Meeting 7, October 9, 2019

Agenda

1. Roll call
2. Presentation: Rex Carr, MD: Pain, fatigue, “Lyme”… How to get out of the maze
3. Upcoming meetings and report development

Overview

The subcommittee heard a presentation from member Rex Carr, MD, on the successful use of antibiotics to treat persistent Lyme disease and potential mechanisms of action and discussed the implications of the findings.

Meeting 8, October 16, 2019

Agenda

1. Roll call
2. Presentation: Ying Zhang, MD, PhD: Developing more effective treatment for persistent Lyme disease
3. Upcoming meetings

Overview

The subcommittee heard a presentation from Ying Zhang, MD, PhD, of Johns Hopkins University on the effectiveness of treating persistent Lyme disease with combination drug therapies that include antibiotics, essential oils, or herbal products that target the persisters of B. burgdorferi, and discussed the implications of the research.

Meeting 9, November 6, 2019

Agenda

1. Roll call
2. Presentation: Brain imaging in Lyme disease
3. Development of subcommittee report to Tick-Borne Disease Working Group
4. Upcoming meetings

Overview

The subcommittee heard a presentation from three members about their experiences with the utility and findings of brain imaging in people with Lyme disease and discussed the implications of the findings.

Meeting 10, November 13, 2019

Agenda

1. Roll call
2. Presentation: Maternal-fetal transmission of Lyme disease
3. Development of subcommittee report to Tick-Borne Disease Working Group
4. Upcoming meetings

Overview

The subcommittee heard a presentation from member Betty Maloney reviewing maternal-fetal transmission of Lyme disease and discussed the implications of the findings.

Meeting 11, November 20, 2019

Agenda

1. Roll call
2. Development of subcommittee report to Tick-Borne Disease Working Group
3. Guest speaker: Paul Auwaerter, MBA, MD
4. Upcoming meetings

Overview

The subcommittee invited Paul Auwaerter, MBA, MD, past president of the Infectious Diseases Society of America, to take part in an open-ended discussion about policies and practices in the diagnosis and treatment of Lyme disease, particularly for people who continue to have symptoms long after the infection (whether treated or untreated).

Meeting 12, December 4, 2019

Agenda

1. Roll call
2. Review of subcommittee report to Tick-Borne Disease Working Group
3. Upcoming meetings and adjournment

Overview

The subcommittee reviewed its draft report to the Working Group and suggested revisions.

Meeting 13, December 18, 2019

Agenda

1. Roll call
2. Review of subcommittee report to Tick-Borne Disease Working Group and voting
3. Next steps and adjournment

Overview

The subcommittee reviewed its draft report to the Working Group and suggested revisions and voted on the contents.