5

Recommendations

The committee’s charge for this report was to study the evidence base for treatments for Lyme infection-associated chronic illnesses (IACI). To this end, the committee reviewed the existing literature (see Appendix C) and obtained input from people living with Lyme IACI, clinicians, and researchers on current knowledge and gaps on the treatment, etiology, and diagnosis of Lyme IACI. Furthermore, the committee considered emerging lessons from Long COVID and other IACI, current knowledge on co-infections and implications for the development and diagnosis of Lyme IACI and explored advances in medicine and biotechnology that may provide solutions to the research gaps for Lyme IACI treatment. The findings and conclusions, based on the committee’s evidence gathering and deliberations, are presented in the preceding chapters of this report. This includes a framework for evaluating and prioritizing clinical research intended to advance diagnostics and therapeutics for Lyme IACI.

In this chapter, the committee makes six recommendations to advance research on Lyme IACI, which will engage different collaborators throughout the research ecosystem, including policy makers, researchers, research institutions, and research funders (Box 5-1). These recommendations are designed to bridge the research gaps and challenges identified by the committee with strategies that have a high potential for accelerating discoveries. Common to all six recommendations is a call for increased coordination and more intentional collaboration, including with people living with Lyme IACI. Therefore, coordination and collaboration are foundational to the implementation of these recommendations. It is the committee’s hope that

this common foundation can help ensure that progress on any one recommendation will facilitate progress on others.

RESEARCH INTO NEW TREATMENTS THAT ALLEVIATE SYMPTOMS

In preparing this report, the committee investigated the existing evidence base on Lyme IACI treatments. The scoping review of that literature base is described in Chapter 2. The existing evidence is from randomized trials, single-arm trials, observational studies, and anecdotal reports. Among them, the committee found that only six trials for Lyme IACI treatment have been performed with the randomization needed to have high confidence in their results (Cameron, 2008; Fallon et al., 2008; Kaplan et al., 2003; Klempner et al., 2001; Krupp et al., 2003; Murray et al., 2022). Five of these six trials evaluated extended courses of antibiotic therapy, and

one evaluated a yoga intervention (Murray et al., 2022). Unfortunately, these studies have not demonstrated a sustained improvement in patients’ symptoms.

Through the scoping review, the committee found that the mechanisms of Lyme IACI remain poorly understood. However, most treatment trials tested interventions that target hypothesized, but currently unproven mechanisms of disease. Research on treatments that are reasonably likely to address the symptoms that contribute to the poor functionality and quality of life reported by people living with Lyme IACI will be critical as studies continue to evaluate the potential mechanisms of Lyme IACI.

To promote the patient-centeredness of future research, engagement with people living with Lyme IACI will be key throughout the process, from the identification of relevant research questions to the dissemination and implementation of results. Lyme IACI research could benefit from incorporating relevant practices and processes of organizations like the Patient-Centered Outcomes Research Institute, for example, as models for the meaningful engagement of patients in research decision-making. The Congressionally Directed Medical Research Programs (CDMRP) Tick-Borne Disease Research Program (TBDRP) has been a leader in patient engagement in Lyme disease research. In their work on tick-borne diseases, CDMRP includes patients and patient advocates in evaluating proposals and making recommendations for funding (CDMRP, 2024).

RECOMMENDATION 1: Research funders should prioritize improving the function and quality of life for people living with Lyme infection-associated chronic illnesses, including the relief of common symptoms, with scientifically supported interventions. To ensure these interventions are supported by robust evidence, clinical studies should be well-designed, randomized trials with appropriate control groups and, whenever possible, include collection of data to help further understanding of disease mechanisms.

STANDARDIZED RESEARCH DEFINITIONS AND METRICS

In Chapter 2 the committee noted a general lack of standardization of research terminologies and approaches for Lyme IACI research. The lack of consensus definitions of the patient populations has resulted in the use of various terminologies and definitions to describe those with Lyme IACI. The PTLDS case definition, which is often used in research, requires that individuals meet specific criteria to establish a consistent and comparable patient group. However, the PTLDS definition excludes individuals in a broader population with similar symptoms, including some with possible Lyme-related IACI (Johnson et al., 2024). People who may have Lyme IACI

but do not meet the PTLDS definition because of an unclear relationship to past Lyme disease or lack of functional impairment are typically excluded from studies, limiting the ability to recruit adequate numbers of representative study participants. Consequently, the relevance and impact of obtained research data may be unknown for the broader Lyme IACI population that does not meet PTLDS criteria. No objective biomarkers have been validated as prognostic or diagnostic tools for Lyme IACI (Fitzgerald et al., 2021). Yet, similar chronic illnesses with a potential infectious trigger, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), where the trigger is often unknown, and Long COVID have developed consensus syndromic definitions that can be useful for clinical research, including

studies aimed at identifying effective therapies in the absence of objective diagnostic tools.

RECOMMENDATION 2: The U.S. Department of Health and Human Services (HHS) should develop consensus research definitions for Lyme infection-associated chronic illnesses (IACI) that address the different strata of the broad range of people living with Lyme IACI.

1. HHS should develop a Lyme IACI definition and subgroup definitions that acknowledge the heterogeneity of these illnesses.
2. HHS should establish a mechanism to regularly review the Lyme IACI literature and update the consensus research definition and subgroup definitions as new evidence emerges.
3. The consensus research definition and subgroup definitions for Lyme IACI should be developed in such a way as to include a broad range of perspectives (e.g., lived experience, clinicians, researchers) and generally align with definitions for other similar conditions and facilitate coordination of research across the diseases.

In the absence of common standards, the committee found that individual Lyme IACI studies tend to evaluate treatments differently. For example, different studies may measure reductions in fatigue but use different

measurement instruments, measure different outcomes entirely, or examine different subsets of the Lyme IACI population. Additionally, existing standard general patient-reported health survey forms, such as the SF-36, have been used in research into Lyme IACI and other IACI with similar symptomatology, but may not always capture symptoms that are important to people living with Lyme IACI. Several symptom questionnaires have been specifically designed for Lyme IACI but have had limited patient involvement in their development. And there are currently no Lyme IACI-specific outcome measurement tools developed for use in children, while the pediatric population differs from adults in terms of physiological and mental development, including the ability to self-report health outcomes. The lack of standardization in outcome measures and tools hinders the ability to compare or combine results from multiple studies, often limiting their informativeness to individual studies. Common data elements (CDE) offer a solution to these challenges by aligning disparate researchers and institutions on outcomes, metrics, and data formats. The development of CDEs for Lyme IACI may be guided by similar efforts that are underway in the field of ME/CFS (NIH, n.d.).

RECOMMENDATION 3: The National Institutes of Health (NIH), in coordination with the Centers for Disease Control and Prevention (CDC), should define a set of standard research tools and metrics to advance research and development of new treatments for Lyme infection-associated chronic illnesses (IACI). These include common data elements (CDEs), sensitive outcome measures, and terminologies that reflect the lived experience of people with Lyme IACI.

1. NIH and CDC should assess, with participation of all interested parties, whether existing patient-reported outcome measurement tools reliably and accurately capture the priority outcomes for people with Lyme IACI, or if new tools and measures are needed. This should include determining if there are groups (e.g., children) for which existing reporting tools do not capture necessary Lyme IACI constructs.
2. NIH and CDC should evaluate existing CDEs from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID for components that can be incorporated into Lyme IACI CDEs to enable knowledge sharing among IACI, including through comparative studies of multiple disease areas. This could include adopting a core set of clinical characteristics for study participants, study methodologies, and symptom reporting questionnaires that mirror those already being used in ME/CFS or Long COVID research.

IMPROVED ACCESS TO BIOBANKS AND REGISTRIES

The committee assessed the role and importance of biobanks and patient registries in facilitating Lyme IACI research. Samples and data from biobanks and registries can serve as valuable research elements for hypothesis generation and for performing treatment and mechanistic studies. Currently, several biobanks and registries exist that collect patient-derived biological samples and clinical and laboratory data from the Lyme IACI patient communities and investigators (Bay Area Lyme Research Foundation, n.d.; Boston Children’s Hospital, n.d.; CUMC, 2025; Johns Hopkins Lyme Disease Research Center, 2025; Molins et al., 2014). However, these samples and data are currently not widely used in Lyme IACI research. Multiple factors likely contribute to the relatively rare use of biobanks and registries. The types of data collected by and contained in biobanks and registries are not consistently made transparent to potential participants and investigators. Furthermore, the heterogeneity of Lyme IACI along with the lack of diagnostic biomarkers increases the need for clear and consistent characterizations of participants and their samples. But the consistency that is needed is hindered by insufficient coordination between biobanks and registries. Promoting quality in the collection and storage of samples and data and paying attention to the responsibility that biobanks and registries owe to participants will play important roles in increasing the value these resources can add to clinical research.

An example from cancer research demonstrates how efforts to promote coordination and standardization among independent biobanks and research groups that collect samples have been an effective means of improving quality and visibility. A centralization initiative with the World Health Organization’s International Agency for Cancer Research Biobank developed a common dataset, a platform of resources housed within the biobank, and a uniform governance structure. These centralization activities improved interoperability between samples and data collected at different sites and increased visibility and accessibility of resources that are stored at disparate sites (Mendy et al., 2019). Importantly, there are practical limitations to the adoption of a central governance structure for Lyme IACI biobanks that would enable a federated biobank network. Many Lyme IACI biobanks are managed by independent research groups, without a central authority to establish uniform governance. However, a federated Lyme IACI biobank is a worthy aspiration as coordination among biobanks takes hold.

RECOMMENDATION 4: To enhance impact in research, funders and managers of biobanks and patient registries for Lyme infection-associated chronic illnesses (IACI) should adopt the following practices that optimize the sustainability of these resources and the accessibility, quality, and utility of their samples.

1. Biobanks should promote awareness, coordination, governance, accessibility, sustainability, and standardization of data and samples from participants with Lyme IACI and those serving as appropriate control groups, including healthy controls and participants with similar conditions or symptoms.
2. Biobanks and patient registries should refine and make public the data domains they capture to increase accessibility and spur collaboration. In sample and data collection, the samples should be characterized in a manner that promotes data quality and confidence in their use. Biological collections associated with individual research studies should follow a standardized set of basic data and metadata domains to facilitate use across studies.
3. Biobanks and patient registries should develop and communicate protocols that describe the intended use of collected samples and data for participants who contribute their data and samples.

COORDINATED RESEARCH FUNDING AND COLLABORATION EFFORTS

Lyme IACI research relies on various funders and is conducted at diverse sites, often resulting in research silos with minimal coordination between different research efforts. The committee found that there is poor integration of research resources such as biobanks and registries with the traditional research infrastructure through which trials are conducted. The lack of coordination between disparate research endeavors hinders knowledge sharing and the ability to constructively build a synergistic evidence base (Coppola et al., 2019).

Other IACI, such as Long COVID and ME/CFS, have coordinating centers that promote research collaboration and knowledge sharing. Lyme IACI research could similarly benefit from promoting and supporting coordination between research sites and investigators to both build synergies and limit redundancy in research, helping make the most of the limited resources available to aid people living with Lyme IACI.

RECOMMENDATION 5: Research funders should support the development and sustainment of a Lyme infection-associated chronic illnesses (IACI) research data-coordinating center that facilitates resource and knowledge sharing across programs conducting Lyme IACI clinical research and incorporates input from people living with Lyme IACI.

1. To further the visibility of biobank resources, the research data coordinating center should collaborate with biobanks on the development of a central repository that catalogues the location and characteristics of available samples and data.

COLLABORATION ACROSS IACI RESEARCH

In Chapter 3, the committee explored research into mechanisms and treatments for other IACI, with a focus on symptom-based interventions. Several disease mechanisms driving IACI symptoms have been hypothesized, including infection-triggered immune dysfunction, pathogen or antigen

persistence, and microbiome dysbiosis. However, there is currently an insufficient understanding of the underlying mechanisms that cause Lyme IACI (Bai and Richardson 2023; Choutka et al., 2022). On the other hand, the overlap in common symptoms between Lyme IACI and other IACI and related conditions is well established, raising the question as to whether there might be commonalities in disease mechanisms underlying shared symptoms. To further explore this, some research is beginning to include multiple IACI populations within a single study (MIT, n.d.; PolyBio, n.d.). The committee considers this a potentially promising approach, as research on different IACI has generally been siloed.

Several initiatives have been implemented to align various partners in the research ecosystem on common goals. The federal government, in coordination with public and private partners—including patient communities—has developed action plans to address many conditions of public health concern and to align research efforts across government, academia, and industry, including the HHS National Action Plan on Long COVID. Further, NIH has recently funded a large prospective longitudinal trial to better understand progression from Lyme disease to Lyme IACI. However, these initiatives lack a cross-IACI collaborative approach that could yield findings that could advance research on multiple conditions simultaneously. As the HHS Office of Long COVID Research and Practice is set to close, a strategic plan will be critical to coordinate and monitor the many IACI research initiatives, and to ensure the efficiency of the complex IACI research ecosystem.

RECOMMENDATION 6: The Department of Health and Human Services (HHS) should develop an integrated strategic plan for infection-associated chronic illnesses (IACI) research that facilitates collaboration across the different disease research efforts. The strategic plan should improve the understanding of commonalities among IACI and identify and advance interventions to address specific conditions, including Lyme IACI. The strategic plan should balance the need for clinical research on treatments, basic and clinical research on disease mechanisms, and incorporation of real-world evidence (RWE).

1. The strategic plan should prioritize the development and support of substantive efforts to improve the treatment and management of IACI symptoms.
2. The strategic plan should include continued investment in large-scale, prospective, multicenter observational studies designed to generate evidence on the mechanistic similarities and differences between Lyme IACI and other IACI, including clinical and laboratory characteristics.
3. To complement prospective studies, the strategic plan should address the opportunity to use RWE, including information based on patient registry data and findings from observational studies.

CLOSING THOUGHTS

In this report, the committee has described its findings, conclusions, and recommendations, which were developed based on its review of the literature, internal discussions, and valuable input from patient representatives, clinicians, and researchers. While Lyme IACI is poorly understood and heterogeneous, patients currently considered under the umbrella of Lyme IACI have a significant burden of symptoms and disability that requires urgent attention.

To get to effective treatments, there is a need for coordinated definitions, research efforts, and resources. While continuing research into the triggers and mechanisms responsible for the development of Lyme IACI is essential, the urgent need for effective interventions requires an enhanced focus on developing therapies to treat those symptoms most debilitating and important to people living with Lyme IACI. Innovative approaches to the design, conduct, and interpretation of studies could be more broadly adopted in Lyme IACI research to expand the breadth and depth of the evidence base. Furthermore, similarities between Lyme IACI and other IACI offer untapped opportunities for Lyme IACI research to build on the successes of research on Long COVID and ME/CFS. These commonalities also warrant coordination and collaboration between researchers studying these various conditions to constructively develop and evaluate their evidence bases together. The committee hopes that their recommendations and proposed research framework can accelerate new developments in the field of Lyme IACI and contribute to the discovery of effective treatments for the many living with this syndrome.

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