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Clinical Presentation and Pathogenesis Subcommittee Report to the Tick-Borne Disease Working Group








  
  
    

  
      





Co-chairs: Jennifer Platt, Ben Beard, and Leith States

*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 potential 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

Tick-borne diseases account for significant morbidity and mortality each year in the United States. Recent studies, based on insurance claims data, estimate that more than 476,000 Lyme disease cases are diagnosed and treated each year (Kugeler et al., 2021). In addition to reported cases, each year deaths occur resulting primarily from Rocky Mountain spotted fever, Powassan virus encephalitis, and Lyme disease carditis (CDC, 2021b, 2021c, 2022b).

In areas where tick-borne diseases are common, patients who present with classic symptoms often receive prompt diagnosis and effective treatment, leading to good clinical outcomes. Unfortunately, symptoms of tick-borne diseases can be missed, and if ineffectively treated or left untreated, disease can progress to more serious illness with persistent and difficult-to-treat symptoms, and even death. Consequently, early, and accurate diagnosis and treatment are critical for successful clinical outcomes. Some of the common reasons for delayed and/or misdiagnosis, specifically related to clinical presentation and subsequent diagnosis, include the following:

Illness was contracted during travel.
	Illness occurred in an area where the disease is emerging and therefore not suspected.
	Clinical presentation was atypical.
	Clinical presentation was not recognized (e.g., rash in a person of color).Currently, six tick-borne diseases are nationally notifiable in the United States, meaning that surveillance data on their occurrence is routinely collected and reported to the Centers for Disease Control and Prevention (CDC) each year. These include the following: Lyme disease, spotted fever rickettsiosis, anaplasmosis/ehrlichiosis, babesiosis, tularemia, and Powassan virus infection. Not all tick-borne diseases are reportable, however, and there are more than 13 bacterial pathogens (Kingry et al., 2020) and another 4 viral pathogens (CDC, 2019b) that are known to cause tick-borne illness in the United States. The majority of these have been discovered in recent years largely due to improved methods for detection and diagnosis and from the increasing numbers of people exposed each year to the bites of infected ticks.

In addition to tick-borne infectious disease, there are emerging tick bite-associated conditions such as Galactose-alpha-1,3-galactose (Alpha-gal) syndrome (AGS), which is triggered in the United States by the bite of the lone star tick *Amblyomma americanum*. AGS has been reported since 2007, from numerous countries in Asia, Australia, Europe, and North America. While the specific cause is yet to be determined, it has been strongly linked globally to the bites of certain tick species. Recent studies indicate increasing trends in diagnosed cases in the United States, with the largest numbers of cases being reported across the central belt of the country, where the lone star tick is very common and frequently bites people (Binder et al., 2021).

Tick-borne diseases are increasing in the United States each year, both in case numbers and in geographic distribution (Beard et al., 2021). Most tick-borne diseases occur in a complex zoonotic life cycle that involves ticks and both large and small mammals or birds, with humans serving as dead-end hosts, meaning that they do not play a significant role in maintenance or emergence of the disease. The drivers for disease emergence are also complex, involving multiple factors, including the following:

Changing land use patterns, including reforestation and suburban growth
	Abundant habitat around homes for reservoir hosts (e.g., rodents)
	Overabundant deer populations
	Increased numbers of ticks
	Increased exposure opportunities in people
	Changing climateAs increasing numbers of people are at risk for tick-borne diseases, particularly in areas where these illnesses may not have been previously established, prompt action must be taken to educate the public and health care community of changing patterns of risk. Health care providers must be equipped with state-of-the-science information on tick-borne diseases in order to provide accurate and timely diagnosis and treatment, thus minimizing the risk of more serious outcomes including death. This information includes local risk of infection, range of clinical presentations, appropriate diagnostic tests and criteria, and safe and effective treatment options.

This subcommittee report examines the challenges, opportunities, and potential actions associated with clinical presentation and pathogenesis of tick-borne illnesses in the United States. Specifically, we focus on the following topic areas:

Mechanisms of pathogenesis including autoimmunity, latency, persistence, and reemergence
	Mental health
	Neurologic and neuropsychiatric manifestations
	Pregnancy and congenital infection
	Lessons to be learned from Post-COVID Sequelae
	Health equityMethods

The purpose of this section is to provide the methods used by the Clinical Presentation and Pathogenesis Subcommittee to prepare its report to the Tick-Borne Disease Working Group.

Characteristics of the Subcommittee

The subcommittee consisted of 10 members including three co-chairs, two from the Federal government and one from the public sector. The remaining 7 members included representatives from public health, academia, patients, patient advocates, and clinical practice.

Subcommittee expertise ranged from those whose experience comes from their profession to those whose personal experiences drive their expertise. Some members were advocates who ran nonprofit organizations, patients, or family members of patients. Health care providers, including clinicians who treat patients with tick-borne diseases and representatives from public health, rounded out the subcommittee (Table 1).

Subcommittee Meetings

The subcommittee scheduled a total of 14 meetings from early October 2021 until March 2022 (Table 2). The co-chairs, in collaboration with the other members, identified several topic areas where they felt expert presenters could provide insight and inform the subcommittee report (Table 3). The co-chairs volunteered to begin drafting the Background and Methods section with help from the support writer.

Public Comment and Inventory

The subcommittee co-chairs analyzed the public comments received from the Public Comments Subcommittee and categorized them as either already addressed, not needing to be addressed, or missing in the report. Pertaining to the Clinical Presentation and Pathogenesis Subcommittee, patients and other members of the public shared an extensive range of tick-borne disease symptoms. They reported symptoms that span all body systems, and vary from mild (e.g., rash, occasional headache, fatigue) to fatal (e.g., anaphylaxis, suicide from depression). Many patients indicated that they are not getting better, despite months and even years of treatment. Others describe periods of latency, after which symptoms return, a phenomenon known in the medical literature as recrudescence.

Subcommittee Report Development

Upon consideration of the report goals, expert presentations, public comments, and current Federal activities, the subcommittee identified priority issues that would serve as the focus of the report. Members volunteered to participate in writing groups devoted to each priority issue. To ensure inclusion of broad stakeholder perspectives, section writers were asked to evaluate divergent viewpoints for which stakeholders do not have consensus.

Using screen share technology and collaboration software, the subcommittee reviewed each writing group’s submission and provided revisions and feedback.

On February 23, 2022, the members discussed, finalized, and voted on each of the individual Potential Actions. All were adopted by unanimous vote. The Results and Potential Actions section was unanimously adopted by members present at the meeting (with one member absent), subject to non-substantive minor edits that might be uncovered before actual submission (Table 4).

Brief for the Working Group

With input from subcommittee members about the most important aspects of the report, the co-chairs developed the slide presentation for the briefing of the Tick-Borne Disease Working Group on March 1, 2022. The Subcommittee’s PowerPoint was completed and submitted to the Working Group on February 24, 2022.

Table 1: Members of the Clinical Presentation and Pathogenesis Subcommittee
	Members
			Type
			Stakeholder Group
			Expertise**Co-Chairs**Charles Ben Beard, MS, PhD
			Federal
			Federal Employee
			Epidemiology, prevention, and control of vector-borne diseases, CDCJennifer Platt, DrPH
			Public
			Patient AdvocateLeith States, MD, MPH, MBA FACPM
			Federal
			Federal Employee Provider
			Preventive medicine, and patient-centered health information technology; Deputy Chief Medical Officer, HHS/OASHMembersMeghan Bradshaw
			Public
			Patient Advocate
			Patient Advocate; MPH Student; Nonprofit board memberSue Faber, RN, BScN
			Public
			Patient Advocate
			Patient Advocate; Co-Founder LymeHope Researcher in Lyme disease and PregnancyBrian Fallon, MD MPH
			Public
			Researcher
			Clinical Researcher; Director, Lyme & TBD Research Center at Columbia University Irving Medical Center; NYS TBD Research PsychiatristAlison Hinckley, PhD
			Federal
			Federal Employee
			Epidemiology, surveillance, and public health; Bacterial vector-borne diseases, CDCJacob Lemieux, MD DPhil
			Public
			Clinician, Researcher
			Clinical infectious diseases, microbial genetics, tick-borne disease, COVID-19Tina Merritt, MD
			Public
			Health Care Provider
			Alpha-gal Syndrome, health care providerRhisa Parera
			Public
			Patient Advocate
			Tick-borne diseases patient

Table 2: Overview of Clinical Presentation and Pathogenesis Subcommittee Meetings
	Meeting No.
			Date
			Present
			Topics Addressed1
			October 7, 2021
			Charles Ben Beard
			Jennifer Platt
			Holiday Goodreau
			Linden Hu
			Megan Bradshaw
			Sue Faber
			Brian Fallon
			Jacob Lemieux
			Rhisa Parera
			Introductions; topics for consideration; potential speakers for upcoming meetings2
			November 3, 2021
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Linden Hu
			Meghan Bradshaw 
			Sue Faber 
			Brian Fallon 
			Alison Hinckley 
			Jacob Lemieux 
			Tina Merritt Meinholtz
			Rhisa Parera
			Presentation from Dr. Brian Fallon, on Neuropsychiatric Lyme Disease; presentation from Dr. Jennifer Platt on Alpha-gal Syndrome; potential and confirmed speakers for upcoming meetings3
			November 17, 2021
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Linden Hu
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Presentation from Dr. Peter Krause on Human Babesiosis; presentation from Dr. Peter Krause on *Borrelia Miyamotoi*4
			December 1, 2021
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Presentation from Ms. Sue Faber on Maternal-Fetal Lyme disease; presentation from Dr. Alison Hinckley on Long Covid conditions5
			December 15, 2021
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Rhisa Parera
			Discussion on Subcommittee Report writing process, outline, potential topics, including symptoms, pathogenesis mechanisms, recrudescence, and neuropsychiatric effects, and chronic conditions of tick-borne disease6
			January 5, 2022
			Charles Ben Beard
			Jennifer Platt
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Presentation from Miranda Lynch-Smith on health equity; Subcommittee discussion on report writing logistics and scheduling.7
			January 12, 2022
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Presentation from Dr. Tina Merritt on Alpha-gal Syndrome; Subcommittee discussion on report writing topics and potential action items.8
			January 19, 2022
			Charles Ben Beard
			Jennifer Platt
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Presentation from Dr. Monica Embers on Borrelia infection during pregnancy; Presentation from Dr. Ross Boyce on tick-borne diseases in the southeast United States; Subcommittee review of report template and discussion of report content9
			January 26, 2022
			Charles Ben Beard
			Jennifer Platt
			Meghan Bradshaw
			Sue Faber
			Jacob Lemieux
			Tina Merritt
			Rhisa Parera
			Recorded presentation from Dr. Scott Commins on Alpha-gal Syndrome; Presentation from Dr. Paul Auwaerter on post-acute sequelae of COVID-19; Subcommittee discussion of SC report writing10
			February 2, 2022
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Subcommittee review of SC report template and discussion of report content11
			February 9, 2022
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Subcommittee discussion of report content12
			February 16, 2022
			Jennifer Platt
			Linden Hu
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Subcommittee discussion of report content and votes on potential action items13
			February 23, 2022
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Subcommittee discussion of report content and votes on report sections14
			March 9, 2022
			Charles Ben Beard
			Jennifer Platt
			Leith States
			Meghan Bradshaw
			Sue Faber
			Brian Fallon
			Alison Hinckley
			Jacob Lemieux
			Tina Merritt
			Subcommittee discussion of report content and final votes on report sections

Table 3: Presenters to the Clinical Presentation and Pathogenesis Subcommittee
	Meeting No.
			Presenter(s)
			Topics Addressed
			Ok to Share?2
			Dr. Brian Fallon, Dr. Jennifer Platt
			Neuropsychiatric aspects of Lyme disease; Alpha-gal Syndrome Survey of Patient Symptoms and Experiences
			Yes3
			Dr. Peter Krause
			Presentation and Pathogenesis of Human Babesiosis and *Borrelia Miyamotoi*
			Yes4
			Ms. Sue Faber, Dr. Alison Hinckley
			Maternal-Fetal Lyme disease; Long Covid Syndrome
			Yes6
			Ms. Miranda Lynch-Smith
			Health Equity
			Yes7
			Dr. Tina Merritt
			Alpha-gal Syndrome
			Yes8
			Dr. Monica Embers, Dr. Ross Boyce
			Borrelia infection during pregnancy; Tick-borne diseases in the southeast United States
			Yes9
			Dr. Scott Commins, Dr. Paul Auwaerter
			Alpha-gal Syndrome; Post-acute sequelae of COVID-1
			YesTable 4: Votes Taken by the Clinical Presentation and Pathogenesis Subcommittee
	Meeting Number or Date
			Motion
			Result In Favor
			Result Opposed
			Result Abstained
			Result Absent
			Minority Response13
			Adopt All Potential Actions in Priority 1
			9
			0
			0
			1
			None13
			Adopt All Potential Actions in Priority 2
			9
			0
			0
			1
			None13
			Adopt All Potential Actions in Priority 3
			9
			0
			0
			1
			None13
			Adopt All Potential Actions in Priority 4
			9
			0
			0
			1
			None13
			Adopt All Potential Actions in Priority 5
			9
			0
			0
			1
			None13
			Adopt All Potential Actions in Priority 6
			9
			0
			0
			1
			None14
			Vote on Background and Methods
			9
			0
			0
			1
			None14
			Vote on Final Report
			9
			0
			0
			1
			NoneResults and Potential Actions

For consideration by the Tick-Borne Disease Working Group, the Clinical Presentation and Pathogenesis Subcommittee has identified six major priorities and 28 potential actions to achieve them.

Priority 1: Mechanisms of pathogenesis including autoimmunity, latency, persistence, and reemergence

The committee identified multiple areas of concern related to clinical presentations and mechanisms of pathogenesis.

*Background*

The geographic distribution and incidence of tick-borne diseases are not well understood, particularly for emerging infections due to *Borrelia miyamotoi,*Powassan virus, and AGS.

*Summary of Evidence and Findings*

Several tick-borne disease pathogens have been newly recognized or distinguished, including *Rickettsia* 364D, *Ehrlichia muris eauclairensis*, *B. miyamotoi*, *B. mayonii*, Heartland virus, and Bourbon virus since the initial descriptions of Lyme disease, babesiosis, and anaplasmosis/ehrlichiosis (Kernif et al., 2016; Li et al., 2015; Pritt et al., 2016, 2017; Rodino et al., 2020). At the same time, clinical manifestations and complications of these emerging tick-borne infections or diseases, as well as those diseases with overlapping clinical presentations and nonspecific serological tests (e.g., spotted fever *Rickettsia* or Lyme disease*)*, are incompletely understood. Complications arising from tick bites, such as AGS, are also increasingly recognized (Commins, 2020). Thus, new research is needed to define the clinical presentation and mechanisms of pathogenesis for these diverse tick-borne pathogens that can infect humans.

*Challenges*

Diagnosis of tick-borne diseases is a challenge. This topic is considered by other subcommittees, including one focused specifically on diagnostics. However, this issue relates to clinical presentation because optimal diagnostics may rely on samples from different anatomic sites or tissues (Rodino et al., 2020). The full spectrum of clinical presentation for various tick-borne diseases, especially the less-recognized diseases such as*B. miyamotoi*disease (also referred to as hard tick relapsing fever) are not completely understood. For example, the duration of spirochetemia is not well-known for *B. miyamotoi*(Karan et al., 2018). This affects whether a polymerase chain reaction (PCR)-based bloodstream diagnostic assay can be used, or whether a serological assay is also needed.

*Opportunities*

The increasing appreciation of the burden of post-infectious syndromes, of great interest to patients with known or possible tick-borne disease, highlights that we have a limited understanding about their mechanisms of pathogenesis. Studies of post-COVID conditions (PCC) have identified multiple disease subtypes/endotypes and identified several potential mechanisms that may contribute, including (1) reactivation of herpesviruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), (2) autoimmunity, and (3) injury due to severe initial burden of disease (Peluso & Deeks, 2022; Su et al., 2022.

Tick-borne diseases are caused by classes of organisms known either to cross the placenta directly or cause adverse neonatal outcomes indirectly, including spirochetes, viruses, and parasites (Joseph et al., 2012; Larsson et al., 2006; Waddell et al., 2018). The subcommittee emphasizes that the spectrum of illness during pregnancy is not completely understood, and mechanisms of pathogenesis unique to pregnancy, including transient immunosuppression/immunomodulation during pregnancy, and the pathogen-placental interface, need further investigation.

Defining mechanisms of pathogenesis is critical because it opens avenues for therapy. For example, if severe initial infection leads to persistent symptoms, then early treatment and vaccination strategies aimed at preventing severe and/or disseminated disease are likely to be effective at reducing persistent symptoms. Alternatively, if autoimmunity plays a role, then immune modulating therapies may be able to ameliorate disease course.

*Priority 1 Potential Actions*

**Potential Action 1.1:** Provide funding to support local, regional, and national investigation and reporting for tick-borne diseases and conditions, including detailed information to include complications and presentation of illness, by the state public health departments and the CDC.

Table 5: Vote on Potential Action 1.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.2:**Support additional research on the mechanisms of pathogenesis of tick-borne disease, with a particular focus on central nervous system infection (including neuropsychiatric illness and neuropathic injury), persistent symptoms, allergy (AGS), immunity, autoimmunity, pregnancy, and adverse fetal outcomes.

Table 6: Vote on Potential Action 1.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.3:**Build on USG “National Strategy” framework to clearly delineate the roles of various federal agencies in describing the clinical presentation of emerging infectious diseases. Specifically, define how the NIH and CDC cooperate to answer research questions at the interface of clinical and translational research and epidemiology of emerging tick-borne diseases.

Table 7: Vote on Potential Action 1.3
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.4:**Establish controlled, prospective studies of tick-borne disease cases during pregnancy and prioritize research studies at the maternal-fetal interface, including the mechanisms of placental injury and transplacental passage by tick-borne pathogens.

Table 8: Vote on Potential Action 1.4
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.5:**Provide funding to support a multi-site, longitudinal study of adults and children to define mechanisms of pathogenesis of post-treatment Lyme disease, using lessons learned from research into PCC.

Table 9: Vote on Potential Action 1.5
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.6:**Allocate dedicated funding and Prioritize research efforts to defining (1) the burden of symptoms and extent of persistent symptoms and (2) disease mechanisms with the goal of disrupting mechanisms of pathogenesis to offer new treatment approaches for patients suffering from sequelae of tick-borne disease.

Table 10: Vote on Potential Action 1.6
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.7:** Ensure that tick-borne disease research and educational efforts include a representative cross-section of patients from a variety of geographic, racial, ethnic, and socioeconomic backgrounds.

Table 11: Vote on Potential Action 1.7
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 1.8:**Invest in research to develop and maintain repositories of biospecimens from patients with well-characterized tick-borne diseases to improve the performance of serological assays and to promote development and validation of newer diagnostic technologies.

Table 12: Vote on Potential Action 1.8
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1Priority 2: Neuropsychiatric Lyme Disease and Mental Health Issues

*Background*

Lyme disease is well-recognized as a localized and systemic illness impacting dermatologic, cardiac, rheumatologic, and neurologic systems. While much is known about the clinical phenotypes that meet the Council of State and Territorial Epidemiologists (CSTE) case definition for Lyme disease, much less is known about other clinical presentations. Most research on Lyme disease uses the CSTE case definition, focusing on objective visible signs (e.g., erythema migrans rash, facial palsy, arthritis). This leads to an abundance of articles using these case definitions, but very little published material about the atypical presentations (Perea et al., 2020). Because the atypical presentations are less well studied, patients with these presentations are at greater risk of delayed diagnosis and treatment. Examples of presentations less well recognized include ophthalmologic (e.g., conjunctivitis, uveitis), neurologic (ischemic stroke, myelitis), neuropsychiatric (reviewed below), and cardiac (e.g., pericarditis) (Kostic et al., 2017; Mikkila et al., 2000; Rothermel et al., 2001; Schwenkenbecher et al., 2017; Smith, 1991; Winward et al., 1989).

Although neuropsychiatric presentations have been reported for more than three decades in the medical literature, rarely are the neuropsychiatric manifestations and mental health needs of Lyme disease described in medical textbooks or on government websites (Fallon & Nields, 1994; Kohler, 1990; Pachner, 1988). Lack of acknowledgement of this aspect of Lyme disease leads to lack of recognition, delayed diagnosis, and treatment, and in some cases severe long-term morbidity or, rarely, death due to suicide.

*Summary of Evidence and Findings*

Lyme borreliosis has been associated with numerous neuropsychiatric manifestations, including depression, suicidal ideation and behavior, anxiety disorders, obsessive-compulsive disorder (OCD), mania, psychosis, sensory hyperacuities, and mild to severe cognitive impairment (Bransfield, 2017; Doshi et al., 2018; Fallon & Nields, 1994; Hassett et al., 2008; Hess et al., 1999; Kohler, 1990; Pachner, 1988; Pasareanu et al., 2012; Tager et al., 2001; Vrethem et al., 2002). These may present before other neurologic or rheumatologic features of Lyme disease have emerged (Hess et al., 1999; Pasareanu et al., 2012) or months to years after antibiotic therapy (Hassett et al., 2008; Pachner, 1988). Early research began with case studies and uncontrolled case series and more recently have expanded to include larger case-control studies and nation-wide cohorts. Most research has focused on cognitive problems and depression. There is much less research on other neuropsychiatric aspects, such as anxiety, sleep disorders, psychosis, and sensory hyperacuities, although a report on neuropsychiatric Lyme disease from a psychiatric outpatient practice suggests that anxiety and sleep disorders in particular are common (Bransfield, 2018).

*Cognitive Aspects*

Concentration problems are reported by about one-quarter of patients in early disseminated Lyme disease (Aucott et al., 2013). Among patients with persistent symptoms (post-treatment Lyme disease syndrome, PTLDS), up to 90% complain of cognitive difficulties (Touradji et al., 2019)but, of these, a smaller percentage (7-30%) have objective measurable problems on neuropsychological batteries. These typically impact short-term memory, verbal fluency, and processing speed (Kaplan et al., 1992; Keilp et al., 2006; Krupp et al., 1991; Touradji et al., 2019). These cognitive deficits have been shown to be independent of depression and on average mild in severity (Barr et al., 1999; Keilp et al., 2019; Ravdin et al., 1996; Westervelt & McCaffrey, 2002).

*Psychiatric Aspects*

*Clinical series and case reports*

Studies of patients with erythema migrans (EM) indicate that depression is typically not a significant initial accompanying feature (Aucott et al., 2013). However, if Lyme disease is not treated early or the initial manifestation is more severe, case reports suggest psychiatric features may emerge and be misdiagnosed as a primary psychiatric disorder. This has been demonstrated in well-documented case reports of mania (Pasareanu et al., 2012), OCD (Pachner, 1988), Tourette’s syndrome (Riedel et al., 1998), and psychosis (Hess et al., 1999); in each of these four cases, psychiatric symptoms resolved after antibiotic therapy. In a 1990 case series of patients with chronic neurologic problems after Lyme disease, neuropsychiatric problems were common—cognitive impairment (89%), depression (37%), sleep disturbance (30%), and extreme irritability (Logigian et al., 1990). These chronic problems emerged months to years after the original *B. burgdorferi* infection. While frank encephalopathy is not common, mild to moderate cognitive problems are frequently seen in all stages of Lyme disease.

*Controlled studies*

Many prior controlled studies have examined different cohorts of patients to assess the association with depression. Some have reported higher rates of depression in children and adults after Lyme borreliosis (Doshi et al., 2018; Hassett et al., 2008; Tager et al., 2001), while others failed to find elevated rates of depressive symptoms (Dersch et al., 2015; Kalish et al., 2001; Schmidt et al., 2015). One cross-sectional study (Cozmo et al., 2017) reported that hospitalized patients with neuroborreliosis had similar rates of depression as hospitalized individuals with Lyme arthritis. One follow-up study (mean 32 months) reported higher rates of depressive symptoms after neuroborreliosis compared to EM after antibiotic treatment (Vrethem et al., 2002). Other follow-up studies, on the other hand, have not found differences in depressive symptoms among individuals 6 months after treatment for EM (Bechtold et al., 2017) or 10-20 years after treatment of EM, facial palsy, or arthritis (Kalish et al., 2001). In general, when acute Lyme disease is recognized quickly, rates of depression at follow-up tend to be low, as shown in studies of early Lyme disease (Aucott et al., 2013).

Studies indicate that rates of suicidal thoughts in patients with PTLDS symptoms range from 20% to 41%. These rates in the case-control studies were significantly higher than reported among patients from other medical illness groups or non-medically ill controls (Bransfield, 2017; Doshi et al., 2018; Tager et al., 2001).

These prior studies varied in quality and suffered from methodological limitations, such as small sample size, use of unvalidated measures, use of poorly specified criteria for the diagnosis of Lyme borreliosis, ascertainment bias, lack of an appropriate control group, reliance on clinical samples, lack of control for confounding variables, or a cross-sectional design.

*Nationwide studies*

To overcome these methodological limitations, researchers recently completed two large nationwide cohort studies using Danish registries.

Study 1. Neuroborreliosis as defined by Bb-specific intrathecal Ab production

This study asked whether individuals with a positive *B. burgdorferi*-specific spinal fluid index subsequently had increased rates of hospital-diagnosed mental disorders, inpatient psychiatric hospitalization, or psychiatric medication prescriptions compared to individuals who had never had a positive intrathecal *B. burgdorferi* index (Tetens et al., 2021). Focusing on the interval from 1995 to 2015, the study identified 2,897 index-positive patients who were then matched to 28,970 controls, for a study population size of 31,876 individuals. The study reported no association with hospital-diagnosed mental disorders or with psychiatric hospitalization, but psychiatric medication prescriptions were increased during the subsequent year (Tetens et al., 2021). The clinical indications for psychiatric medication prescriptions are not recorded in the Danish registry; the authors speculated these were for pain, sleep, or mood issues. This study, by design, did not include the non-neurologic manifestations of Lyme borreliosis.

Study 2. Lyme disease as defined by a hospital-based diagnosis.

The authors of this retrospective cohort study asked whether individuals with a hospital-based diagnosis of Lyme borreliosis (i.e., inpatient, outpatient, or emergency room) had increased risk of any subsequent mental disorder, affective disorder, suicidal behavior, and death by suicide compared to individuals who had never had a hospital-based diagnosis of Lyme disease (Fallon et al., 2021). Focusing on all persons living in Denmark from 1994 to 2016, there were 6,945,837 individuals in the study (12,616 with Lyme disease and 6,933,221 without Lyme disease). By including the entire population of Denmark during that interval, this research design bypassed many of the limitations of prior studies. Because the investigators were interested in examining new onset mental disorders after Lyme borreliosis, individuals with a pre-Lyme disease history of a diagnosed mental disorder or suicide attempt were excluded. The study found a 28% higher rate of any mental disorder, a 42% higher rate of affective disorder, 2-fold higher rate of suicide attempts, and a 75% higher rate of death by suicide after the hospital-based diagnosis of Lyme borreliosis, compared to those without a hospital-based diagnosis of Lyme borreliosis. To examine whether comorbid disorders other than Lyme disease were contributing to increased rate of mental disorders, a sensitivity analysis was conducted that revealed that a similarly increased risk of mental disorders and suicide after Lyme borreliosis diagnosis remained even when those with pre-Lyme major medical morbidity were removed from the analysis.

A dose-response relationship was noted in the above study such that more than one episode of Lyme borreliosis increased the incidence rate ratio (IRR) of any mental disorder to 79%. A temporal relationship was also noted, such that the IRR for any mental disorder was highest at 96% during the first six months after the initial hospital diagnosis of Lyme disease; although the rate declined over time, it was still elevated with an IRR of 19% five years after the first diagnosis. While causation cannot be concluded, the presence of both a dose-response relationship and a temporal relationship to the occurrence of mental disorders added strength to the likelihood of a causation between Lyme borreliosis and mental disorders. It should be noted that because the Danish registry only records hospital-based diagnoses, the results of this study may not apply to individuals treated solely in the community setting. This study may reflect the impact of more severe Lyme disease rather than the mild cases.

As in study 1, a relationship between mental disorder diagnosis and neuroborreliosis was not found. However, study 1 did find an increased rate of psychiatric prescriptions in the year after the Lyme neuroborreliosis diagnosis, suggesting that neuropsychiatric sequelae were recognized and treated in the community setting rather than the hospital.

*Sensory and Autonomic Aspects*

Sensory dysfunction and autonomic problems may be seen with post-treatment Lyme disease. For example, in a clinical series of 10 individuals with PTLDS (Novak et al., 2019), all had abnormalities in the following: skin biopsies for nerve fiber density (9/10 epidermal and 5/10 sweat gland); functional autonomic testing (10/10); cerebral perfusion velocity was abnormally low (via transcranial Doppler) (10/10). A small clinical series of 10 patients with Lyme neuropathy reported a reduction in pain with oral gabapentin therapy (Weissenbacher et al., 2005). A research poster presentation at the American Academy of Neurology in 2009 by Katz and Berkley described a clinical series of 30 patients who were assessed for neuropathic pain and treated with intravenous (IV) immunoglobulin therapy; each of the patients had OspA reactivity (either due to Lyme disease [n=22] or a prior Lyme vaccine). The research, published as an abstract in a supplement in *Neurology*, reported improvement in subjective clinical symptoms and objective small nerve fiber density at 6 months (Katz & Berkley, 2009). Aside from these reports, little is known about small fiber neuropathy in Lyme disease.

*Mechanisms of Neuropsychiatric Disease*

Neuropsychiatric sequelae may be due to active infection or post-infectious processes. Acute or persistent *B. burgdorferi*or remnants of the bacteria can trigger inflammation (systemic and/or central), autoimmunity (e.g., molecular mimicry), or alterations in central nervous system (CNS) metabolism and/or blood flow. One or more of these biologic mechanisms can cause neuropsychiatric problems. Other factors may also contribute, such as current stressors (pain, economic, interpersonal), uncertainty about diagnostic tests and treatment options, genetic factors, and prior medical and trauma history (Mustafiz et al., 2021).

Decreased brain blood flow and metabolism have been demonstrated in studies of Lyme encephalopathy and PTLDS (Fallon et al., 2009; Logigian et al., 1997; Novak et al., 2019). Peripheral markers of inflammation and immune mediators may remain elevated long after initial antibiotic therapy among patient with PTLDS, such as C-reactive protein (CRP) (Uhde et al., 2016), interferon alpha (Jacek et al., 2013), chemokine ligand 19 (CCL19) (Aucott et al., 2016), and interleukin 23 (IL-23) (Strle et al., 2014). CNS inflammation in PTLDS has also been demonstrated through positron emission tomography (PET) imaging studies (Coughlin et al., 2018), indicating microglial activation. Autoimmunity, a prominent mechanism in late Lyme arthritis (Strle et al., 2017), may also contribute to neuropsychiatric symptoms, because certain *B. burgdorferi*surface proteins and neural tissue share homology that can lead to cross-reactivity (Alaedini & Latov, 2005; Garcia-Monco et al., 1995; Raveche et al., 2005; Sigal, 1993). The serum of patients with PTLDS has high levels of anti-neuronal antibodies with binding to cells in the peripheral and central nervous system (Chandra et al., 2010). Multiple prior episodes of Lyme disease may contribute to an immune priming effect, leading to elevated anti-neuronal autoantibodies and increased neuronal cell signaling (Fallon et al., 2020).

*Conclusions*

Lyme encephalitis can have diverse manifestations, including neuropsychiatric ones, that may be misdiagnosed as a primary psychiatric disorder. Early localized Lyme disease generally does not have significant psychiatric features. Among the 5-20% of patients with persistent symptoms despite antibiotic treatment for Lyme disease, cognitive and psychiatric features can be prominent and disabling. Although suicide after Lyme disease is not common and the absolute risk is low, the rate in the Danish study was increased by 75% among those with a hospital-based diagnosis of Lyme disease; this is of obvious concern (Fallon et al., 2021). The period of greatest risk for mental disorders is the first year after hospital-based diagnosis, but the risk remains elevated for several years. The literature therefore supports the need for an increased recognition that Lyme disease can impact mental health and potentially contribute to suicide.

*Challenges*

*Descriptive and Pathogenesis Research Challenges*

Insufficient research on the neurologic and neuropsychiatric profile of those with persistent symptoms attributed to other non-Lyme vector-borne-related microbes (e.g., *B. miyamotoi*, *Bartonella* species).
	Insufficient research on predisposing factors that may contribute to cognitive and other neuropsychiatric symptoms.
	Paucity of research on neuropsychiatric autoimmune disease triggered by *B. burgdorferi*infection.
	Insufficient research on how Lyme disease alters/impacts the brain.
	Insufficient research on how tick-borne diseases impact the mental health of immigrant and other marginalized communities.*Treatment Research Challenges*

**Cognitive problems**. Early uncontrolled studies on Lyme encephalopathy demonstrated that intravenous ceftriaxone therapy led to an improvement in cognition and an improvement in cerebral blood flow on single-photon emission computerized tomography (SPECT) imaging (Logigian, 1997). A controlled treatment study of persistent Lyme encephalopathy with 10 weeks of IV ceftriaxone (n=37) (Fallon et al., 2008) revealed cognitive improvement at 12 weeks (p=.053), but loss of cognitive gains by 24 weeks. Because of the paucity of studies, little is known about how to treat the long-term cognitive problems associated with Lyme disease.
	**Psychiatric problems**. There have not been any studies focused on the treatment of depression, anxiety, or other psychiatric problems related to persistent symptoms despite antibiotic therapy in Lyme disease. The clinical treatment options range from pharmacotherapy, brain stimulation, psychotherapy, antibiotic therapy, immune modulatory therapy, or a combination of these.
	**Sensory and autonomic problems**. There are only two reports to our knowledge of a clinical series assessing non-antibiotic treatment of persistent Lyme disease-related neuropathic pain, one using gabapentin (Weissenbacher et al., 2005) and another using IV immunoglobulin (Katz & Berkley, 2009); these had positive results and small sample sizes. Given the recent finding that 10/10 patients with Lyme-related neuropathic pain demonstrated small fiber neuropathy and problems with autonomic function (Novak et al., 2019), this area requires more research.*Mental Health Challenges*

Lack of recognition by medical professionals of the neuropsychiatric aspects of Lyme disease and of the areas of uncertainty in Lyme disease (e.g., poor inter-lab reliability; how to treat persistent or relapsing symptoms).
	Lack of acknowledgement by medical professionals of the evidence supporting persistent Lyme disease-related symptoms and of areas of uncertainty. This leads to an experience of invalidation by the patient and mistrust in the doctor-patient relationship.
	Stigma associated with mental illness may prevent patients from obtaining care.*Opportunities*

COVID-19 has led to a wider acceptance of the validity of infection-related neuropsychiatric syndromes. This will be taught in health care training. Lyme disease can be added as another microbe associated with persistent symptoms.
	Collaboration with COVID-19 research colleagues on biomarker studies can enhance the study of both diseases because Lyme disease would be an excellent comparator group.
	COVID-19 has made clear that there can be multiple differing mechanisms underlying persistent symptoms. Ranging from persistent infection to post-infectious mechanisms (damage, ongoing inflammation, antibody-mediated disease, altered neural circuitry). Treatment needs to address the primary mechanism of ongoing symptoms.
	Treatment strategies could be shared via a think tank. Given similarities between PCC and PTLDS symptoms, it is likely that similar treatment approaches may be of benefit to individuals and help to inform both diseases.*Priority 2 Potential Actions*

**Priority Action 2.1:**Provide funding to support research on mechanisms leading to, and perpetuating, neuropsychiatric disease among individuals with Lyme disease and/or other emerging vector-borne diseases reported among individuals with tick-borne illness.

Table 13: Vote on Potential Action 2.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Priority Action 2.2:**Provide funding to support research on treatment of neuropsychiatric disease related to Lyme disease and/or other emerging vector-borne diseases reported among individuals with tick-borne illness.

Table 14: Vote on Potential Action 2.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Priority Action 2.3:**Provide funding to support collaborative research studies among investigators of different infection-related syndromes, focusing on shared mechanisms of disease between Lyme disease and other “Long Hauler” syndromes (e.g., autoimmunity, inflammation, autonomic dysregulation, damage, microbial persistence).

Table 15: Vote on Potential Action 2.3
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Priority Action 2.4:**Provide funding to support research on individuals with acute or persistent symptoms attributed to tick-borne illness (but who may not have received a definitive diagnosis) to better characterize, understand, and treat this large group of patients.

Table 16: Vote on Potential Action 2.4
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Priority Action 2.5:**Provide funding to develop educational modules and update state and federal websites for health care professionals and trainees on the knowns and unknowns (including mental health aspects) regarding Lyme disease and other emerging vector-borne diseases that are reported among individuals with tick-borne illness.

Table 17: Vote on Potential Action 2.5
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Priority Action 2.6:**Provide funding to support research investigating the prevalence of undetected tick-borne illness among subgroups of the population that may have a high burden of multi-systemic chronic conditions (e.g., mental illness, musculoskeletal diseases) that has been inadequately medically evaluated (e.g., individuals in psychiatric facilities, prisons, homeless shelters, other populations experiencing health disparities).

Table 18: Vote on Potential Action 2.6
	**Number in Favor**
			**Number Opposed**
			**Number Abstained**
			**Number Absent**9
			0
			0
			1Priority 3: Pathogenesis and Clinical Presentation of Allergy to Galactose-alpha-1,3-galactose (Alpha-gal Syndrome)

*Background*

The story about AGS in the United States starts with life-threatening allergic reactions to a cancer drug, which was later found to contain a mammal carbohydrate, Alpha-gal. Significant overlap was observed between the location of known cases of allergy to Alpha-gal and cases of spotted fever rickettsiosis and ehrlichiosis. These diseases can be transmitted by the tick species *A. americanum* (lone star tick). This led investigators in the United States to associate bites from the lone star tick with an allergic response to Alpha-gal, a carbohydrate present on mammals except humans and higher apes. The syndrome is caused by bites from adult and immature ticks. People who develop AGS may develop symptoms upon exposure to red meat, mammal products, and certain medications (Platts-Mills et al, 2020).

Patients used the Working Group’s public comment process to share an extensive range of tick-borne disease symptoms. Symptoms range across all body systems, and vary from mild (e.g., rash, occasional headache, fatigue) to fatal (e.g., anaphylaxis, suicide from depression). In addition, many patients indicated that they are not getting better, despite months and even years of treatment. After a period of latency, others may experience a return of symptoms, known in the medical literature as recrudescence or reactivation. Co-infections need to be considered in patients with AGS who are still having symptoms, as well as other causes of chronic inflammation.

*Summary of Evidence and Findings*

The saliva of certain species of ticks have been found to contain Alpha-gal. New research confirms the presence of Alpha-gal in the lone star tick’s saliva (Sharma & Karim, 2021). Significantly, the study also reveals the presence of Alpha-gal in the saliva of the black-legged tick (*Ixodes scapularis*). The black-legged tick, which is heavily concentrated in the northeastern United States, is primarily known to transmit Lyme disease. The discovery that it may also transmit Alpha-gal has important implications for the diagnosis and treatment of patients for Lyme disease and other tick-borne diseases in the United States. Both tick species are expanding their territory, and the reported cases of AGS are expanding as well (Platts-Mills et al., 2018).

*Pathogenesis*

The pathogenesis of reactions to Alpha-gal involves getting sensitized, or becoming allergic to Alpha-gal, followed by the immune response after becoming allergic. In a recent paper (Carson et al., 2022), the proposed immune mechanism for developing AGS is described. During feeding, tick mouth parts induce physical trauma to the skin while introducing Alpha-gal, potentially disease-causing bacteria, and other particles that alter the immune response. This may trigger the production of chemicals (cytokines) that promote an allergic response. The immune response to the tick saliva converts the antibody-producing cells (B cells) in some people to switch to produce IgE, the allergy antibody.

Symptoms of food allergies differ significantly, depending on the immune mechanism involved and the affected target organ (Anvari et al., 2019). Severe symptoms include shortness of breath, wheezing, and repetitive cough. Blood pressure may decrease, but in a subset of patients with AGS, their blood pressure increases during a reaction (Tick-Borne Conditions United, 2022). Some people with AGS are extremely sensitive and report dizziness and even loss of consciousness with minimal exposure. Neurologic symptoms include feeling something bad is about to happen, anxiety, and confusion. Urticaria or hives are red, raised rashes that itch, but some patients with AGS report burning with the rash. Gut symptoms include acute cramping pain, nausea, vomiting, and severe diarrhea. Not everyone with AGS has a life-threatening reaction. The symptoms of AGS are usually delayed 3-6 hours after eating red meat or mammal ingredients such as gelatin (Commins & Platts-Mills, 2013). Another confounding factor is that the level of allergy antibody against Alpha-gal does not always correspond with the level of reaction. A positive test result for IgE to Alpha-gal is greater than 0.10 kU/L.

*Challenges*

Public commenters often refer to the fear and frustration associated with AGS. It is unique to their condition because it extends far beyond simply avoiding the consumption of red meat. Many people must worry about medications, products, and cross-contamination, which limits their daily lives.

It is unclear how many people have AGS, but specimens from 105,674 persons were tested for Alpha-gal IgE during July 1, 2010, to December 31, 2018. Nearly one-third (34,256, 32.4%) had at least one positive result (Binder et al., 2021). In a recent survey, the five most common reactants were beef, pork, dairy, gelatin (usually in medications), and personal care products. While 25% experienced reactions 4-6 hours after exposure, 7% also indicated reactions within 0-5 minutes. Exposure routes included ingestion, topical, and inhalation. Two-fifths of respondents have visited the emergency room due to reactions; 37% had 15 or more reactions prior to diagnosis; and 25% still react once or more a month after diagnosis. The top autonomic (neurologic) symptoms include abnormal sweating and fainting. Greater than 60% reported anxiety. To learn how to prevent further reactions, 50% of patients get online support while 20% receive information from health care providers. (Platt & Merritt, 2022).

*Priority 3 Potential Actions*

**Potential Action 3.1:** Provide continuing education to health care professionals (primary care providers, emergency providers, specialists, and subspecialists) and the general community on risk and recognition and testing for Alpha-gal allergy and tick-borne co-infections.

Table 19: Vote on Potential Action 3.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 3.2:** Educate patients about symptoms and avoidance measures, including avoiding tick bites, and an action plan on how to treat an allergic reaction.

Table 20: Vote on Potential Action 3.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 3.3:** Develop a food management operations protocol around food allergies to include standardized staff training and education, ingredient/allergen identification, critical control points for cross contact, consumer information and first aid. Allergen Management plans should be documented and reviewed as part of routine oversight through local health inspection agencies. This will likely be an interagency collaboration including USDA and FDA and other HHS operating divisions.

Table 21: Vote on Potential Action 3.3
	**Number in Favor**
			**Number Opposed**
			**Number Abstained**
			**Number Absent**9
			0
			0
			1**Potential Action 3.4:** Labeling requirements, for the protection of consumers, must include at the minimum this statement, “this product contains mammal by-product”, for any food, alcohol, beverage, medical, hygiene, beauty, or textile product that has been processed with or contains any mammalian derivative. This will necessitate action by the FDA and the Bureau of Alcohol, Tobacco, Firearms, and Explosives. Create an easy to identify symbol that indicates a product contains mammal by-product. Create a comprehensive list of all mammal ingredient names that is public and easily accessed.

Table 22: Vote on Potential Action 3.4
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 3.5:**Funding to agencies such HRSA and CDC to educate clinicians and pharmacists across the training continuum about mammal ingredients in medications.

Table 23: Vote on Potential Action 3.5
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 3.6:** Continued support for research into the pathogenesis of Alpha-gal allergy.

Table 24: Vote on Potential Action 3.6
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1Priority 4: Pregnancy and Lyme Disease

*Background*

Lyme disease and pregnancy is an issue of special concern and importance given that both mother and baby are at a particularly sensitive time for health and development. The Lyme disease bacteria, *B. burgdorferi*, can be transmitted vertically, from mother, across the placenta, to offspring. This has been documented in animals [1]1
 and humans [2], with many experts providing reviews, professional opinion, and analysis on the subject matter [3]. In the current edition of a leading medical reference textbook on the subject matter of infectious diseases of the fetus and newborn infant, experts recommend expansion of “TORCH” the well-known medical acronym for the group of diseases that are known to cause congenital infections to “TORCHES-CLAP” with “L” representing Lyme disease (Wilson et al., 2014). Transplacental transmission of *B. burgdorferi* may invariably challenge and expand what is known regarding the pathogenesis and resulting clinical spectrum of Lyme disease (Hamilton, 1989; Harvey & Salvato, 2003; Jasik et al., 2015).

This alternate mode of transmission, albeit considered rare in humans, is acknowledged by CDC (2020), NIH (2008), and Health Canada (2022). CDC currently estimates that 476,000 people (2022a) are infected with Lyme disease each year in the United States; however, it is currently unknown what proportion of those diagnoses may occur in pregnant women and to what extent their pregnancy or developing baby may be affected. Limited research into this alternate mode of transmission in the past 25 years has resulted in significant data gaps, as well as a lack of clinical guidance and resources for health care providers. Impacted patient populations often struggle to access appropriate diagnosis, treatment, and care (Gaudet et al., 2019). Given the lack of high-quality, reproducible clinical and epidemiologic research on this topic, a standardized definition for congenital Lyme infection has not been established.

*Summary of Evidence and Findings*

A systematic review of the evidence of congenital tick-borne disease infection was outside the subcommittee’s scope. However, the subcommittee reviewed the summary findings from numerous articles, which are partly summarized below to capture both the breadth of work in this area and the limitations of currently available evidence.

The pathophysiological properties of *B. burgdorferi* include the ability of the spirochete to adhere to and migrate through endothelial surfaces including human umbilical cord and the amniotic membrane (Agus, 1995; Garcia-Monco & Benach, 1989; Szczepanski et al., 1990). Similar findings of spirochetes invading intercellular junctions of endothelial cells in-vitro have been reported with the spirochetal organism, *Treponema pallidum*, the agent of syphilis (Thomas et al., 1988).  A report on the histopathological findings of Lyme borreliosis highlights the risk of transplacental transmission of *B. burgdorferi*with spirochetes identified in fetal tissues upon autopsy. Authors also report unpublished findings of decidual necrosis with inflammation in patients with intrauterine infection due to *B. burgdorferi* (De Koning & Duray, 1993).

Autopsy findings from cases of congenital Lyme disease (MacDonald, 1989; MacDonald et al., 1987; Schlesinger et al., 1985; Weber et al., 1988) have reported *B. burgdorferi* spirochetes in fetal/infant tissue specimens with minimal or lack of inflammatory infiltrates or cell response (De Koning & Duray, 1993), including descriptions of pathological findings associated with gestational and congenital Lyme disease (Duray & Steere, 1986; 1988). Minimal inflammatory response despite *B. burgdorferi* spirochetal presence has also been reported in experimental studies of hamsters infected intraperitoneally (Duray & Johnson, 1986), beagle pups/fetuses infected in-utero (Gustafson et al., 1993), biopsy samples from human brain tissue (Pachner et al., 1989), and a case of latent Lyme neuroborreliosis (Pfister et al., 1989) where the organism was cultured and isolated from the cerebral spinal fluid of a patient without accompanying inflammatory changes.

Spirochetal invasion of fetal tissue without a corresponding inflammatory response is not unique to *B. burgdorferi* because it has also been reported with *T. pallidum* in cases of congenital syphilis (Harter & Benirschke, 1976; Stowens, 1959). One investigator hypothesizes that this phenomenon occurs as the result of a human fetus being “immunologically incompetent” to respond to foreign antigen in early gestation (Silverstein, 1962, 1973), thus resulting in an inability to mount an immunologic response to a foreign organism. Interestingly, absence of inflammation despite Zika virus infection has recently been identified in placentas from fetuses with congenital Zika virus infection (Schwartz, 2017).

Adverse pregnancy outcomes reported with gestational Lyme disease include spontaneous abortion, stillbirth, premature delivery, neonatal death, intrauterine growth restriction, and varying conditions or defects in the newborn ranging from low birth weight and hyperbilirubinemia to hypotonia, newborn sepsis, cerebral bleeding, hydrocephalus, cardiovascular and urinary tract defects, long-bone abnormalities, ophthalmic and neurologic abnormalities, respiratory distress, and newborn rash [4].  An analysis (up to year 2001) of 66 cases of gestational Lyme borreliosis with corresponding fetal or neonatal adverse events identified an overall 23% incidence of cardiac malformations, 15% rate of neurologic abnormalities, 12% incidence of orthopedic abnormalities, 11% incidence of genitourinary abnormalities, and 9% rate of maculopapular rash. Thirty-six percent of the total number of adverse outcomes were miscarriages or neonatal deaths. Illness in the newborn included early onset sepsis, and later onset chronic progressive symptoms were also reported (Gardner, 2001). The March of Dimes provides information on Lyme disease and pregnancy on its website and lists potential complications in untreated pregnancy, including infection of the placenta, stillbirth, congenital heart defects, urinary tract defects, jaundice, and newborn rash (March of Dimes, 2017).

A study from Hungary reported on outcomes of 95 women with Lyme borreliosis during their pregnancy (Lakos & Solymosi, 2010). Of this group, adverse pregnancy outcomes were documented in 12.1% of women treated with IV antibiotics, 31.6% of women treated with oral antibiotics, and in 60.0% of women who remained untreated. A heterogeneous range of adverse outcomes was described including spontaneous abortion, stillbirth, preterm birth, neonatal jaundice, cavernous hemangioma, papulovesicular rash at birth, cerebral bleeding, and muscular hypotonicity. Authors mention that placentas and offspring were not tested for *Borrelia* by PCR or culture in their study; however, cord blood was tested by immunoblot in 74 patients, and none of the tested newborns exhibited a cord blood IgM reaction.

Prospectively acquired data from Slovenia, reported findings from 304 women diagnosed with an EM rash in pregnancy, a majority of whom were treated with IV ceftriaxone (Maraspin et al., 2020). Of this group, 42 women (13.8%) experienced unfavorable pregnancy outcomes listed as preterm birth (52.4%), fetal/perinatal death (23.8%), and/or other anomalies (35.7%) including cardiac and genitourinary abnormalities. In several cases, other potential causes for adverse outcomes were identified. Authors stated that they did not perform direct detection of *Borrelia* in fetal tissue or umbilical blood and identified this as a limitation of their study. No control groups were included in either of these studies to provide for direct comparison of adverse outcome rates with those of the reference populations.

While prompt diagnosis and treatment of Lyme disease in pregnancy most often corresponds with healthy pregnancy outcomes [5], evidence of *B. burgdorferi* infection in placentae, fetus, or baby has been reported despite varying courses and types of maternal antibiotic treatment, raising concerns of treatment failure and disease persistence [6]. Thus, research efforts must focus on identifying safe and effective therapeutics that not only eliminate infection in the mother, but also prevent both transplacental transfer of the spirochete to the fetus and corresponding sequalae [7]. Recent evaluation of the impact of antibiotic treatment on birth outcomes of women infected with *B.* *burgdorferi* during pregnancy using data from numerous past epidemiological studies (Waddell et al., 2018) has provided additional indirect support for an association between gestational Lyme disease and adverse birth outcomes with a meta-analysis identifying “significantly fewer adverse birth outcomes in women reported to have been treated for gestational Lyme disease (11%, 95%CI 7-16) compared to those who were not treated during pregnancy (50%, 95%CI 30-70).”

The clinical presentation of Lyme disease may look somewhat different during pregnancy. A study in pregnant mice infected with *B. burgdorferi* (Moro et al., 2001) reported an attenuated pathogenic inflammatory response associated with Lyme arthritis. A recent report in humans identified a milder course of constitutional symptoms accompanying an EM rash in pregnancy compared to age-matched non-pregnant women (Maraspin et al., 2020). Given that asymptomatic/subclinical infection with Lyme disease has been clearly demonstrated in the broader population [8], the impact of asymptomatic or latent Lyme disease infection in pregnancy must also be considered and closely examined. Reports of subclinical or asymptomatic maternal Lyme disease coupled with fetal/infant infection have been documented [9].

Evidence for transmission of Lyme disease during pregnancy in humans has included identification of spirochetes, *Borrelia spp, or B. burgdorferi* in autopsy specimens of heart, kidney, liver, brain, bone marrow, and spleen from fetal (Horowitz & Yunker, 2003; MacDonald, 1986, 1989; MacDonald et al., 1987; Maraspin et al., 1999; Neubert, 1987) or neonate tissue (Lavoie et al., 1987; MacDonald, 1989; Maraspin et al., 1999; Schlesinger et al., 1985; Weber et al., 1988) using culture (MacDonald, 1986; MacDonald et al., 1987; Lavoie et al., 1987), PCR (Horowitz & Yunker, 2003) and indirect immunofluorescence (with specific monoclonal antibodies including H5332, which is specific to outer surface protein A [P31] of *B. burgdorferi*  and does not cross react with relapsing fever *Borrelia*, leptospires, or treponemes) (Barbour et al., 1983; MacDonald, 1986, 1989; MacDonald et al., 1987; Weber et al., 1988). Several cases of live birth (following maternal infection) and descriptions of congenital infection have also been documented [10]. *B. burgdorferi-*specific antibodies have been identified in cord blood (Hulínska et al., 2009), infant blood (Horst, 1992), and cerebral spinal fluid of symptomatic neonates (Dattwyler et al., 1989; Horst, 1992). PCR testing revealed evidence of *B. burgdorferi* in cord blood from infants whose mothers had been treated for Lyme disease in their pregnancy (Vanousova et al., 2007). *B. burgdorferi*has also been identified by histology (Burrascano, 1993; MacDonald, 1989; Patmas, 1994), PCR [11], and/or electron microscopy in placentas of pregnancies treated and untreated for Lyme disease. *B. burgdorferi* has also been identified by PCR in human breast milk (Schmidt et al., 1995), but cases of transmission through breastfeeding have not been reported. A 1996 study of placentas (Figueroa et al., 1996) revealed positive identification of *B. burgdorferi* by silver-staining and PCR in a small subset of seronegative, asymptomatic pregnancies, which raises questions regarding silent transmission of the spirochete.

Evidence for in utero transmission of *B. burgdorferi*, reproductive failure, and adverse birth outcomes has been reported in natural animal populations of mice (Anderson et al., 1987; Burgess et al., 1993; Wan, 1999), rats (Wan, 1999), cows (Burgess, 1988; Leibstein et al., 1998), horses (Burgess et al., 1989), vixens (Gustafson, 1993), and coyotes (Burgess & Windberg, 1989). Findings from experimental models in mice include maternal-fetal transmission of *B. burgdorferi* via the placenta in 57% of fetuses or stillborn pups (Ubico-Navas, 1992); a 10.2% rate of in utero or intrapartum transmission of *B. burgdorferi* and an 8% rate of its transmission via milk (Altaie et al., 1997); and an association between murine fetal death and acute infection with *B. burgdorferi* in early gestation (Silver et al., 1995). An experimental study in dogs reported both reproductive failure as well as vertical transmission of the spirochete (Gustafson et al., 1993). Four other experimental animal studies did not show transplacental transmission in mice (Mather et al., 1991; Wright & Nielsen, 1980), rats (Moody & Barthold, 1991), and hamsters (Woodrum & Oliver, 1999).

*Challenges*

Despite the previous research into Lyme disease and pregnancy involving animals and humans, several questions regarding occurrence and pathogenesis are yet to be answered. Past studies have suffered from generalizability issues, small sample sizes, inappropriate or no control groups, and limited laboratory evidence. Neither a causal association between gestational Lyme disease and specific adverse pregnancy outcomes nor a homogeneous congenital syndrome in exposed infants has been identified [12].  However, in many larger studies, *B. burgdorferi-*specific direct detection methodologies were not utilized to test exposed infants, placentas, or products of conception/autopsy specimens, resulting in lack of data to assess/determine a possible teratogenic effect or causal association [13]. A framework grouping clinical features and manifestations of pregnancy outcomes complicated by gestational Lyme borreliosis has been proposed (Gardner, 2001). Standardized clinical guidelines providing detailed recommendations for diagnosis, treatment, and follow-up of Lyme borreliosis for both mother and exposed fetus/infant have not been created, as has been done for other emerging infectious diseases such as Zika virus and West Nile virus (CDC, 2004; Staples et al., 2016). This lack of clinical guidance may result in health care practitioners being uncertain how to manage cases of gestational or congenital Lyme disease and may inadvertently lead to barriers to patients accessing timely, appropriate treatment, and care (Gaudet et al., 2019).

Identification of a specific phenotype or syndrome associated with congenital Lyme disease infection would be helpful for diagnosis and treatment of affected infants, but the lack of such a syndrome does not preclude congenital infection and a reliance on a such a syndrome may miss cases. For example, in congenital syphilis, in the post-penicillin era, an attenuated, less obvious clinical presentation in infants is observed (Wicher & Wicher, 2001), and a large percentage of infants born to untreated mothers with syphilis are asymptomatic and appear healthy without evidence of infection at birth. However, if left untreated, they may develop later stages of the disease months to years later (Cooper & Sanchez, 2018). In the instance of congenital Chagas’ disease, no defining clinical syndrome has been identified, and infants with congenital *Trypanosoma cruzi* infection are often asymptomatic or have subtle, non-specific manifestations (CDC, 2012; Livingston et al., 2021).

Developmental monitoring, surveillance, and longitudinal follow-up of infants born to mothers with gestational Lyme disease has not been studied, and little is known about potential growth and neurologic sequalae in this group. One group of researchers (Gerber & Zalneraitis, 1994) suggested this research and knowledge gap be prioritized through “a large, prospective longitudinal investigation of pregnant women with Lyme disease that utilizes sensitive measures for both the diagnosis of Lyme disease and the identification of neurologic disorders could help to determine the precise incidence of Lyme disease during pregnancy, the rate of transplacental transmission of *B. burgdorferi,* and the full implications of transplacental transmission for the infant.” According to Souza and Bale (1995), “based on the apparent tissue tropism of *B. burgdorferi* in children and adults, neurologic or cardiac disease might be predicted as a consequence of congenital infections.” Trock and colleagues (1989) state, “the development of these infants warrants further observation, especially since in another spirochetal infection, congenital syphilis, abnormalities are not always evident at birth.” Lessons learned from other congenital infections underscore the importance of longitudinal assessment and monitoring of exposed infants as complications or abnormalities may not be evident at birth and may develop months or even many years later in life [14].

Past research into Lyme disease and pregnancy has been constrained by use of imprecise or imperfect laboratory diagnostic tools. Early research used staining or serology to indicate evidence of infection when these tools could not reliably distinguish *B. burgdorferi* from other spirochetal infections, other cross-reactive organisms, or non-specific immune reactions [15]. Several past studies (Lakos & Solymosi, 2010; Nadal et al., 1989; Strobino et al., 1993; Williams et al., 1988, 1995) on Lyme disease and pregnancy utilized cord-blood IgM as the only testing mechanism to screen for evidence of congenital infection in exposed infants. IgM antibodies do not cross the placenta and thus, if present, would be an indicator of fetal/neonate response to intrauterine infection (Ostrander & Bale, 2019). In all cases, negative results were reported; however, the sensitivity and specificity of serologic tests to detect *Borrelia-*specific antibodies in newborns is unknown.

In other congenital infections, infant IgM antibody is of limited diagnostic value, and a negative IgM is not used as a stand-alone measure to exclude or rule-out congenital infection (Maldonado & Read, 2017; Revello & Gerna, 2002; Rodrigues et al., 2009). In the case of congenital syphilis, CDC currently recommends against commercially available IgM testing (CDC, 2021a) with an earlier report by CDC authors (Kaufman et al., 1974) identifying a false-negative rate that may exceed 35% in delayed-onset disease, thus insufficient for use as a screening test. It has also been identified that a fetus infected in early gestation, may be unable to produce a sufficient IgM antibody response to infection (Alford et al., 1969; Foulon et al., 1999; Naessens et al., 1999). Diagnostic criteria for other congenital infections cast a wide net beyond cord blood IgM, including PCR, diagnostic imaging, nucleic acid testing from various maternal samples including placenta and amniotic fluid, and neonate samples including saliva, cerebrospinal fluid (CSF), peripheral blood, and urine (Ford-Jones, 1999; Souza & Bale, 1995; Wilson et al., 2014).

Significant data gaps remain regarding how Lyme disease impacts pregnancy in cases of acute versus late-stage or subclinical illness. Questions remain regarding sensitive diagnostic and effective treatment approaches in both mother and baby. Very little information exists on the potential for long-term health impacts of babies born to mothers with gestational Lyme disease. All of these gaps must be filled by alerting the scientific and clinical community to the known risks as highlighted in this section, as well as dedicated funding of collaborative research in this area.

*Opportunities*

In 2020, the Tick-Borne Disease Working Group considered the issue of maternal-fetal transmission of Lyme disease and congenital Lyme disease. It recommended that funding be provided for a registry and for more studies to determine the extent of maternal-fetal transmission of Lyme disease and of any congenital Lyme disease. Since that time, CDC has begun efforts to understand the incidence and impact of Lyme disease during pregnancy. However, much remains to be investigated to clarify the extent of adverse events associated with maternal or congenital infection and the pathogenesis of *B. burgdorferi* during pregnancy. With the potential actions provided in this report, this subcommittee proposes to provide more clarity and momentum to the proposed public health and research aims on this topic. Given the recent advances in diagnostic testing for Lyme disease (e.g., improvements in serologic testing and PCR), it is now time to revisit and re-evaluate what is understood regarding Lyme disease during pregnancy and congenital infections.

The development of evidence-based interim clinical guidelines for Lyme disease in pregnancy could provide health care practitioners with resources and guidance in several important areas, such as (a) clinical evaluation and treatment of Lyme disease in pregnant persons; (b) evaluation of the fetus in pregnant persons with a Lyme disease diagnosis during pregnancy; (c) clinical evaluation and testing of infants born to persons diagnosed with Lyme disease during pregnancy; (d) recommended long-term follow-up for infants with possible congenital Lyme disease infection; and (e) recommendations for histological examination/testing of placenta, umbilical cord, and/or products of conception or other autopsy samples. All of these guidelines could be updated with the emergence of new research or clinical findings.

Unified recommendations by multiple investigators have highlighted the importance and necessity for further research including prospective longitudinal cohort studies [16]. A detailed recommendation from one expert, states “determination of true risk to the fetus and infant of maternal gestational Lyme disease requires prospective studies of all pregnancy outcomes of gestational Lyme disease, long-term follow-up of live-born products of these pregnancies and improved diagnosis of Lyme disease in affected fetuses, placentas and infants” (Gardner, 2001).

Specific funding for studies that elucidate the role of Lyme disease during pregnancy could focus on pathogenesis and maternal/fetal/neonatal immune responses to infection, evaluate the potential for active infection/in-utero transmission of *B. burgdorferi*in pregnant persons with past or subclinical infection, identify potential biomarkers of congenital infection, and investigate safe and effective therapeutics. These efforts could draw new attention to the significance of the issue and further encourage and attract new research on this topic. In addition, funding for specimen biorepositories to include products of pregnancy, as well as relevant maternal and infant specimens would make samples available to clinical investigators for further study or development of specific diagnostics.

Detailed clinical investigation and research collaboration that is aligned with patient-centric study design (Largent et al., 2018) will better define appropriate diagnostics and therapeutics, as well as inform clinical education and management of both the exposed mother and baby, ultimately providing much needed medical care, support, and hope for families and children impacted. It will also provide more clarity around the incidence, clinical spectrum, and potential long-term health consequences of infants exposed to Lyme disease in utero.

*Priority 4 Potential Actions*

**Potential Action 4.1:** Convene a multidisciplinary expert forum to review evidence, identify research gaps, with a goal of establishing interim guidelines for evaluation, testing, and management of infants born to mothers who have a Lyme borreliosis and/or other tick-borne diseases diagnosed during their pregnancy.

Table 25: Vote on Potential Action 4.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 4.2:**  Provide funding for prospective cohort studies of women infected with Lyme disease during pregnancy and their offspring to understand the effects of this infection on maternal health, as well as child health and development.

Table 26: Vote on Potential Action 4.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 4.3:**  Provide funding for RFA studies focused on Lyme disease and pregnancy including maternal/fetal/placental pathophysiology and clinical outcomes, immune responses of disease, possible biomarkers of congenital infection, and efficacy of therapeutics.

Table 27: Vote on Potential Action 4.3
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 4.4:**  Provide funding to support development and maintenance of repositories of specimens from pregnant and lactating persons including placenta, breast milk, cord blood, and autopsy specimens for Lyme disease and tick-borne diseases research.

Table 28: Vote on Potential Action 4.4
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1Priority 5: Clinical Comparisons of Long-hauler Syndromes Related to COVID-19 and Lyme Disease to Elucidate Mechanisms of Disease

*Background*

The subcommittee considered the emerging science on PCC, also known as post-acute sequelae SARS-CoV-2 infection (PASC), long COVID, or long-haul COVID-19. Many patients who have recently experienced a SARS CoV-2 infection report persistent symptoms, referred to here as PCC, that are highly debilitating and of unclear etiopathogenesis. The most commonly reported persisting symptoms of PCC are also frequently reported by patients diagnosed with chronic Lyme disease, as well as other post-infectious viral and non-viral illnesses. These symptoms include fatigue, post-exertional malaise, and cognitive impairment, among others. Given this array of overlapping symptoms, studies regarding the clinical similarities and common etiologies for PCC and chronic Lyme disease may provide insights into an improved clinical management of patients attributing illness to chronic Lyme disease, as well as other post-infectious illnesses.

*Summary of Evidence and Findings*

*Incidence of PCC*

Given the recent occurrence of COVID-19 and recognition of PCC, few longitudinal studies with appropriate control groups have been conducted to determine the incidence of this disease. Of those studies, differing durations of evaluation, as well as different patient outcomes and study methodologies, have limited the ability to generalize findings. Nevertheless, taken together, published studies have suggested a range of 7-22% of confirmed COVID-19 patients continue to have symptoms past 28 days (Chevinsky et al., 2021; Sudre et al., 2021; Wanga et al., 2021). In a study by Chevinsky et al. (2021), in the 1 to 4 months past an initial COVID-19 hospitalization, 7.0% of adults experienced ≥1 of 5 PCC. The proportion was slightly higher (7.7%) for adult outpatients experiencing ≥1 of 10 PCC during that same timeframe. In a study by Sudre at al. (2021), 558 (13.3%) participants self-reported symptoms lasting more than a month, though this number declined to 2.3% at greater than 3 months post-infection.

*Clinical presentation and characteristics of patients diagnosed with PCC*

Risk factors associated with development of PCC are not yet clear. However, preliminary studies suggest that age, female sex, number or severity of early symptoms, and some pre-existing conditions may be associated with an increased likelihood of developing this condition.

In Sudre et al. (2021), PCC was most often characterized as fatigue, headache, dyspnea, and anosmia.  It was more likely to occur with increasing age and body mass index, and female sex. Experiencing more than five symptoms during the initial phases of COVID illness was associated with development of prolonged symptoms (odds ratio = 3.53 [2.76–4.50]). This study employed prospective logging of symptoms and determined that the proportion of people affected by prolonged symptoms is substantial and does not vary according to cultural practice. Risk factors of those experiencing PCC included being older, being female, and having required a hospital assessment.

Huang et al. (2021) prospectively evaluated a cohort of adults hospitalized due to COVID-19 and compared long-term outcomes to controls (non-COVID-19 participants) matched on age, sex, and comorbidities. At 12 months, COVID-19 survivors had more symptoms, including problems with mobility, pain, or anxiety or depression, compared with controls. Moreover, the odds of specific PCC symptoms (fatigue or muscle weakness, anxiety or depression, and diffusion impairment) was higher among women than men.

In the United Kingdom, additional estimates are available regarding the prevalence of symptoms that remain 12 weeks after SARS-CoV-2 infection (Office for National Statistics, 2021). Reported occurrence of persistent symptoms range from 3.0% to 11.7% based on self-classification of long COVID and specific symptoms (using data to August 1, 2021). Prevalence of persistent symptoms was highest in females, older adults (aged 50 to 69 years), people with a pre-existing condition, and those with signs of higher viral load at infection.

*Pathogenesis of PCC and comparison to other post-infectious conditions*

PCCs are generally believed to be caused by either long-term damage to tissues (e.g., lung, brain, and heart) or pathological inflammation (e.g., from viral persistence, immune dysregulation, and autoimmunity) (Yong, 2021). This is similar to what has been proposed for symptoms attributed to chronic Lyme disease, as well as other post-infectious fatiguing illnesses.

In a 2006 publication, Hickie et al. reported on a prospective cohort study that evaluated patients from the time of acute infection with three very different infectious agents: Epstein-Barr virus, *Coxiella burnetii*, and Ross River virus. At six months post-infection, they found prolonged illness (disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance) in 12% of participants. Moreover, 11% met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype occurred at a similar incidence after each infection. In this study, the severity of the acute illness was the only factor found to predict prolonged fatiguing illness. A relatively consistent post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with different viral and non-viral micro-organisms. Given the substantial differences in infecting organisms and relative consistency of symptoms persisting over time, this study strongly suggested that the prolonged response may be due to the host response to infection (rather than the pathogen itself).

In two studies of patients with either a presumed diagnosis or concern for Lyme disease (Kobayashi et al., 2019) or a diagnosis based on alternative testing or criteria (Patrick et al., 2015), misdiagnosis of Lyme disease was suggested as a common finding given likelihood of other overlapping complex conditions. In both studies, the patients were more likely to be female and to have ongoing and numerous symptoms. In the large patient population referred to an academic center and studied by Kobayashi et al. (2019), patients determined not to have active or recent Lyme disease were also more likely to have had alternative laboratory testing and have been diagnosed with coinfections. In the smaller patient population evaluated by Patrick et al. (2015), alternatively diagnosed Lyme disease patients were found to experience significant disability and had a similar phenotype to that of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Given the overlap of ME/CFS and other post-acute fatiguing illnesses with chronic Lyme disease, the possibility of misdiagnosis or similar pathologies for these persistent illnesses exists. Studies to evaluate the etiology of these shared symptoms and pathogenesis of post-acute diseases are crucial to identify the best path forward for management and treatment.

*Challenges*

Without prompt action, lessons learned regarding PCC diagnosis and clinical management that may be pertinent to other post-infectious illnesses, such as chronic Lyme disease, will not be quickly adopted or available for these existing patient groups—groups that might greatly benefit. Therefore, the subcommittee discussed a potential action, which is proposed to the Working Group.

*Opportunities*

The clinical burden of PCC continues to increase as the COVID-19 pandemic persists. Given the enormous impact of COVID-19 on the population, a small percentage of infections developing into PCC will represent a very large number of affected. Further, recognition of PCC is leading to a new understanding and awareness among clinicians regarding the potential burden, depth, and disability of post-infectious illnesses. Already, significant financial and scientific resources are being devoted to evaluating the etiologies of PCC, as well as the management of this disease. If post-infectious disease processes share common etiologies, much could be learned across the myriad of existing chronic conditions that pre-date PCC. Studies to evaluate clinical similarities and common etiologies for PCC and symptoms attributed to chronic Lyme disease may provide insights into improved clinical management of patients experiencing chronic Lyme disease, as well as other post-infectious illnesses.

*Priority 5 Potential Actions*

**Potential Action 5.1:** Provide funding for prospective studies that evaluate clinical similarities, mechanisms of pathogenesis, common etiologies for PCC, other post-infectious fatiguing illnesses, post-treatment Lyme disease, and chronic symptoms attributed to Lyme disease and other tick-borne diseases.

Table 29: Vote on Potential Action 5.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1Priority 6: Health Equity in People Who Are Medically Underserved and the Impacts on Clinical Presentation and Pathogenesis

*Background*

An understanding of the clinical presentation and pathogenesis of tick-borne diseases is an essential step to ensuring that patients receive the best care. It is apparent that many gaps exist in understanding the wide array of clinical symptoms and signs of tick-borne diseases, both in patients who have received antibiotic treatment and in those without any prior antibiotic treatment. Further, presentation of clinical symptoms and pathogenesis in Black, Indigenous, and persons of color (BIPOC) and other underserved groups has received little written or pictorial representation in the research literature.

In the Tick-Borne Disease Working Group’s 2018 Report to Congress, Recommendation 7.2 states that these populations are “particularly vulnerable to tick-borne disease for a variety of reasons. They should be of special consideration when allocating funds for research, treatment, and prevention” (Tick-Borne Disease Working Group, 2018). The President’s Executive Order #13985 on Advancing Racial Equity and Support for Underserved Communities through the Federal Government, signed on January 20, 2021, further defines underserved groups as follows: “Black, Latino, and Indigenous and Native American persons, Asian Americans and Pacific Islanders and other persons of color; members of religious minorities; lesbian, gay, bisexual, transgender, and queer (LGBTQ+) persons; persons with disabilities; persons who live in rural areas; and persons otherwise adversely affected by persistent poverty or inequality” (Exec. Order No. 13985, 2021).

Structural and social determinants of inequity lead to individual- and community-level disparities that further complicate the tick-borne disease patient experience. According to CDC (2019), structural determinants are defined as “processes and policies that lead to unfair practices, such as inequitable distribution of funding across communities. Social Determinants of Health (SDOH) include health, income, employment, housing, environment quality, education, transportation, etc.” (CDC, 2021d; HHS, 2022). These barriers are contributing factors to challenges that patients experience such as delayed or improper diagnosis, exasperation, protracted treatment-chronicity, mental health, disability, and even death.

*Summary of Evidence and Findings*

A review of the literature shows scant evidence of research that includes clinical presentation and pathogenesis in underserved groups. In addition, the absence of reported incidence of tick-borne diseases in these groups adversely impacts the ability to determine accurate information about clinical presentation. The disparate evidence of presentation in underserved groups directly influences the ability of clinicians and researchers to study and learn about pathogenesis in these populations. Note that due to lack of literature this discussion does not include examples of some underserved groups such as persons with disabilities and persons experiencing homelessness. Brouqui and Raoult (2006), who discuss exposure to a range of vector-borne diseases by the homeless or the inner-city poor, assert “Virtually, no data are available on tick-borne disease in this population.”

As noted by researchers, data regarding incidence in BIPOC populations is not accurate due to systemic problems in reporting. For example, Dahlgreen (2011) notes that because BIPOC likely have reduced access to care, “interpreting associations between reported incidence of rickettsial infections with race and ethnicity may be confounded by access to care.” Further, in a study of incidence of *E. chaffeensis*and *E. ewingii* Infections, Nichols (2016) reports that incidence in race and ethnic groups could not even be included in the incidence ratio analysis due to missing data. A study of Rocky Mountain spotted fever (RMSF) incidence in the United States touches on the importance of having accurate data. It found that American Indians were four times as likely to develop RMSF as Whites and had a four-fold greater risk of fatality (Openshaw et. al, 2010). What is yet to be determined is the influences of increased access to health care due to the Affordable Care Act (Angier et. al, 2017).

Race is a social determinant of health. It may be a key factor that explains some of the racial disparities in rates of reported cases of Lyme disease and other tick-borne conditions. Bias of providers who believe that Lyme and other tick-borne diseases are relatively rare in BIPOC also likely contributes to the differential reporting. The reported incidence of Lyme disease among Black people in the United States is substantially below that of White people. According to CDC’s most recent report (2019a), reported and probable cases in the United States by race show the highest prevalence of Lyme disease among White patients with 18,601 reported cases. There were 92 reported cases among Native Americans/Alaska Natives, 492 cases among Asian/Pacific Islanders, 373 among Black patients, and 572 reported as Other.

According to the CDC, the erythema migrans rash is considered to be an early sign or symptom of a tick bite. This EM rash may appear 3-30 days after a tick bite. It is worth noting that the EM rash does not always occur after a bite—only 70-80% of patients will experience this symptom. Additionally, not every EM rash is alike, and presentation can vary greatly. Because patients of color are grossly underrepresented in medical education materials, most clinical education depicts the EM on White patients (Nolen, 2019). This may lead to providers failing to detect early signs of the disease in BIPOC patients, which may play a large role in the under-recognition of Lyme disease in people of color. One study conducted by Johns Hopkins explored Lyme disease in Maryland residents. White patients with Lyme disease were more likely to have noted EM (the “bullseye rash”) at 69.7%, compared to only 25% of Black patients. White patients were less likely to have had arthritis (20.9%), than Black patients (56.5%). Overall, cases with arthritis were significantly less likely to have noted EM than were those without arthritis (17.0 and 81.9 percent, respectively) (Fix et al., 2000).

The study found that among the manifestations of Lyme disease, the greatest difference was for incidence of EM, both across the state and on the Upper Eastern Shore (rural Maryland). However, on the Upper Eastern Shore, the incidence for extracutaneous manifestations was approximately equal, and that for arthritis was greater among Black patients than among White patients (Fix et al., 2000).

Another study explored claims data of Medicare beneficiaries who had a new diagnosis of Lyme disease in 2016 (Ly, 2021). It found that neurological manifestations were reported in 34% of Black patients and only 9% of White patients. The Black-White difference in having disseminated disease was 20.7%. Black patients seem to be diagnosed with disseminated disease more often than White patients in this study (Ly, 2021).

Parallel to the vast lack of incidence data is the lack of prevalence data for underserved groups. There is no way to know prevalence among underserved groups who also face structural and social barriers that create inequities in access to proper diagnostics and care. One example in the literature of prevalence in underserved groups is Graf et al.’s analysis of a serum repository of 10,000 diverse military personnel, which found a significant difference in multivariate analysis of prevalence of Rocky Mountain spotted fever in Black individuals (8.7%, compared with 5.6% among White individuals) (2008).

*Opportunities and Challenges*

The foundational challenge for health equity in persons with tick-borne diseases and conditions is the overall lack of data for all populations defined in Executive Order 13985. Improved data will allow researchers to better understand incidence and prevalence in underserved groups. Accordingly, improvements can take place in clinical presentation and pathogenesis. An improved understanding of the clinical presentation and pathogenesis of tick-borne diseases will support patients in underserved groups in receiving improved care. Five Potential Actions are presented to the Working Group for consideration.

*Priority 6 Potential Actions*

**Potential Action 6.1:** Provide funding to expand communication materials to include minority populations and update health care clinical training and educational materials to address race/characteristic-based tick-borne disease presentations.

Table 30: Vote on Potential Action 6.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 6.2:** Provide funding to update tick-borne and other commonly-associated vector-borne diseases education, prevention materials, and outreach programs for high-risk populations such as pregnant and immunocompromised people; Indigenous, immigrant and migrant farming communities; urban and rural poor; and persons experiencing homelessness. Materials should be available in a variety of languages and culturally appropriate for the intended audience.

Table 31: Vote on Potential Action 6.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 6.3:** Funding to expand bartonellosis education among clinicians and high-risk patients, for example, persons experiencing homelessness and individuals who are immunosuppressed and/or immunocompromised.

Table 32: Vote on Potential Action 6.3
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 6.4:** To require new studies on tick-borne diseases in humans to address health equity concerns, including the following, as appropriate: Conduct/include a retrospective assessment to understand disparities and their root causes; Account for intersectional issues; Evaluate methods for blind spots and consider mixed methods research to remove or reduce them; Strive to have research teams mirror/represent the populations/research questions of focus.

Table 33: Vote on Potential Action 6.4
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1**Potential Action 6.5:** Funding to develop equity-oriented educational materials on prevention for schools and communities.

Table 34: Vote on Potential Action 6.5
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent9
			0
			0
			1Appendix A

References and Citations

Agus, B. (1995). The recognition and treatment of Lyme disease. *Primary Care Update for Ob/Gyns, 2*(6), 200-203. https://doi.org/10.1016/1068-607X(95)00041-G

Alaedini, A., & Latov, N. (2005). Antibodies against OspA epitopes of *Borrelia burgdorferi* cross-react with neural tissue. *Journal of Neuroimmunology, 159*(1–2), 192–195. https://doi.org/10.1016/J.JNEUROIM.2004.10.014

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Appendix B

Citations of Six or More from “Pregnancy and Lyme Disease” Section

(Complete references are available in Appendix A.)

[1] Altaie et al., 1997; Anderson et al., 1987; Burgess, 1988; Burgess et al., 1989, 1993, 1989; Gustafson, 1993; Gustafson et al, 1993; Leibstein et al., 1998; Silver et al., 1995; Ubico-Navas, 1992; Wan, 1999

[2] Dattwyler et al., 1989; Gardner, 2001; Gasser et al., 1994; Horowitz & Yunker, 2003; Horst, 1992; Jones et al., 2005; Lampert, 1986; Lavoie et al., 1987; Lazebnik & Zal’tsman, 2005; MacDonald, 1986, 1989; MacDonald et al., 1987; Maraspin et al., 1999; Neubert, 1987; Önk et al., 2005; Schlesinger et al., 1985; Spector et al., 1993; Trevison et al., 1997; Weber et al., 1988

[3] ACOG, 1992; Alexander & Cox, 1995; Aoki & Holland, 1989; Bale et al., 1992; Belani & Regelmann, 1989; Bennett, 1995; Burgdorfer, 1986, 1991; Cartter et al., 1989; Christen & Hanefeld, 1993; Dauby & Merchant, 2020; De Koning & Duray, 1993; Dennis, 1992; Dotters-Katz et al., 2013; Duray & Steere, 1986, 1988; Edly, 1990; Eichenfield & Athreya, 1989; Elliott et al., 2001; Hercogova & Vanousova, 2008; Johnson, 1993; Jovanic et al., 1993; Kullberg et al., 2020; Luft & Dattwyler, 1989; MacDonald, 1987; McGowan & Hodinka, 1992; Moore et al., 1998; Mylonas et al., 2011; Nadelman & Wormser, 1990; O’Brien & Martens, 2014; O’Kelly & Lambert, 2020; Ostroy & Athreya, 1991; Plotkin et al., 1991; Qasba et al., 2011; Rahn, 1991; Relic & Relic, 2012; Salzman & Rubin, 1991; Schell & Davis, 1989; Schutzer et al., 1991; Shapiro & Gerber, 2006; Silver, 1997; Sliwa, 2011; Smith et al., 1991; Sood, 1999; Souza & Bale, 1995; State of Connecticut Department of Health Services, 1989; Swingler, 2000; Theiler et al., 2008; Trock et al., 1989; Underwood, 1993; Utenkova, 2016; Waddell et al., 2018; Walsh et al., 2007; Weber, 1989; Williams & Strobino, 1990

[4] Bracero et al., 1992; Carlomagno et al., 1988; CDC, 1991; Dattwyler et al., 1989; Dlesk & Broste, 1989; Gardner, 2001; Elsukova et al., 1994; Gasser et al., 1994; Gerber & Zalneraitis, 1994; Goldenberg et al., 2010; Hercogovà et al., 1993; Horowitz & Yunker, 2003; Horst, 1992; Jones et al., 2005; Kaslow, 1992; Lakos & Solymosi, 2010; Lampert, 1986; Lavoie et al., 1987; Lazebnik & Zal’tsman, 2005; MacDonald, 1986, 1989; MacDonald et al., 1987; Maraspin et al., 1999, 2020; Markowitz et al., 1986; McClure et al., 2010; Nadal et al., 1989; Neubert, 1987; Önk et al., 2005; Royal College of Obstetricians and Gynecologists, 2010; Schlesinger et al., 1985; Spector et al., 1993; Strobino et al., 1993, 1999; Trevison et al., 1997; Troyano-Luque et al., 2014; Weber; 1988; Williams et al., 1988, 1995; Zjevikova, 2012

[5] Berger, 1986; Buitrago et al., 1998; Horowitz et al., 2021; Hu et al., 2015; Lakos & Solymosi, 2010; Luger, 1990; Maraspin et al., 2020; Mikkleson & Palle, 1987; Moniuszko et al., 2012; O’Brien & Baum, 2017; Remy et al., 1994; Schaumann et al., 1999; Schutzer et al., 1991; Stiernstedt, 1990; Tsai et al., 2002; Walsh et al., 2007

[6] Burrascano, 1993; Dattwyler et al., 1989; Gardner, 2001; Hercogova & Vanousova, 2008; Horowitz & Yunker, 2003; Hulínská et al., 2009, 2011; MacDonald, 1989; Maraspin et al., 1999; Patmas, 1994; Spector et al., 1993; Vanousova et al., 2007; Weber et al., 1988)

[7] Conforti et al., 2019; Hercogova & Vanousova, 2008; Lavoie, 1991; Luft et al., 1989; Neubert, 1989; Rahn & Malawista, 1991; Sicuranza & Baker, 1993; Wormser, 1990

[8] Burek et al., 1992; Carlsson et al., 2018; Fahrer et al., 1991; Feder et al., 1995; Hanrahan et al., 1984; Huycke et al., 1992; O’Connor et al., 1993; Sigal, 2003; Steere et al., 1986, 2003; Tan et al., 2012; Wilhelmsson et al., 2016

[9] Dattwyler et al., 1989; Horst, 1992 Lampert, 1986; Lavoie et al., 1987; MacDonald, 1986, 1989; Maraspin et al., 1999; Önk et al., 2005; Trevison et al., 1997

[10] Dattwyler et al., 1989; Gardner, 2001; Gasser et al., 1994; Horst, 1992; Jones et al., 2005; Lampert, 1986; Lavoie et al., 1987; Lazebnik & Zal’tsman, 2005; MacDonald, 1989; Maraspin et al., 1999; Önk et al., 2005; Schlesinger et al., 1985; Spector et al., 1993; Trevison et al., 1997; Weber et al., 1988

[11] Hercogova & Vanousova, 2008; Horowitz & Yunker, 2003; Hulínská et al., 2009, 2011; Spector et al., 1993; Vanousova et al., 2007

[12] Elliott et al., 2001; Kimberlin et al., 2021; Lantos et al., 2021; Mylonas, 2011; Shapiro & Gerber, 2006; Silver, 1997; Walsh et al., 2007

[13] Bracero et al., 1992; Carlomagno et al., 1988; Lakos & Solymosi, 2010; Maraspin et al., 2020; Markowitz et al., 1986; Nadal et al., 1989; Strobino et al., 1993; Williams et al., 1988, 1995

[14] Cevallos & Hernández, 2014; Chess, 1977; Cooper & Sánchez, 2018; Montoya & Remington, 2008; Nielsen-Saines et al., 2019; Wilson et al., 2014

[15] Carlomagno et al., 1988; CDC, 1995; Dlesk et al., 1989; Lakos & Solymosi, 2010; Londero et al., 1998; Maraspin et al., 2020; Nadal et al., 1989; Strobino et al., 1993; Williams et al., 1995

[16] Bale & Murph, 1992; Cartter et al., 1989; Edly, 1990; Figueroa et al., 1996; Gardner, 2001; Lakos & Solymosi, 2010; Lambert, 2020; Luft & Dattwyler, 1989; Markowitz et al., 1986; Silver, 1997; Waddell et al., 2018


1. In this section on Pregnancy and Lyme Disease, when more than five references are cited, the references are provided in Appendix B. back to note 1

                    
  


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