Charting a Path Toward New Treatments for Lyme Infection-Associated Chronic Illnesses (2025)
Chapter: Appendix C: Methodology of Literature Review
Appendix C
Methodology of Literature Review
There are currently no safe and effective treatments or diagnostics for Lyme infection-associated chronic illnesses (IACI). Research remains necessary to elucidate the underlying mechanisms and develop new treatments and diagnostic tests for Lyme IACI patients. These efforts may be buoyed by exploring research approaches and findings from commonalities with other similar conditions such as Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
At the request of the Steven & Alexandra Cohen Foundation, an ad hoc committee convened by the National Academies was tasked to examine the existing evidence and knowledge gaps on the etiology and treatment of Lyme IACI and to identify opportunities for learning from similar conditions that can accelerate development of new treatments for Lyme IACI. To explore opportunities where new knowledge can be applied toward accelerating treatment development for Lyme IACI, the committee determined that it was necessary to have an overview of the current evidence and gaps in the Lyme IACI research landscape. The committee structured their approach to addressing this charge into three components:
- Landscape mapping of research related to understanding the etiology and diagnosis of Lyme IACI in humans.
- Landscape mapping of clinical trials from Lyme IACI that tested treatments for persistent symptoms with the greatest impact for those living with Lyme IACI.
- Landscape mapping of clinical trials from other similar conditions, with a focus on Long COVID and ME/CFS, that address the priority symptoms that Lyme IACI shares with these conditions.
To address the first two components, the committee conducted a scoping review of the literature. To address the third component, and in line with the research prioritization principles discussed in Chapter 4, where potential treatments for Lyme IACI that draw from another disease area should be supported by established evidence of efficacy, the committee surveyed recent systematic reviews (since 2020) to identify treatments for ME/CFS and Long COVID that have shown efficacy in randomized controlled clinical trials.
A scoping review is an efficient and appropriate approach to assess the existing evidence base and analyze knowledge gaps. A preliminary search of PubMed did not reveal current scoping reviews on the etiology, treatment, or diagnosis of Lyme IACI in North America; the only available and relevant record is a scoping review that examined the prevalence of reporting on neuropsychiatric manifestations and cognitive decline and the association of delayed diagnosis with symptom severity, in patients with longstanding Lyme disease (Brackett et al., 2024).
The scoping review was carried out by research librarians at the National Academies with consultant research methodologists from PICO Portal and the National Academies study staff, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). The survey of systematic reviews for ME/CFS and Long COVID was performed by the National Academies study staff and research librarians with assistance from the PICO Portal software service for records de-duplication and management. The method for the scoping review and strategy for survey of systematic reviews are detailed below.
SCOPING REVIEW
Literature Search Strategy
The purpose of this scoping review is to identify and characterize peer-reviewed primary research published between 1970 and May 2024 that attempted to elucidate potential pathophysiology mechanisms that underlie symptoms of Lyme IACI or to assess the efficacy of treatments and diagnostics for adults and children with Lyme IACI in North America. A supplemental search was conducted in August 2024 to expand the search terms to include those used in older publications and to identify articles published since the initial search using the updated set of search terms.
Due to the differences in the causative agents and potential implications for disease presentation and long-term manifestations, the committee limited the literature review to North America and excluded studies of Lyme IACI in Europe and elsewhere in the world. Articles were limited to the English language. Databases searched include PubMed, Medline (Ovid), Embase (Ovid), and Scopus.
A standard definition for Lyme IACI does not exist, but it is essential to describe the population that would be included in this literature review. For the purpose of this study, the committee describes the population included in the literature review under this operational scope: that “Lyme infection-associated chronic illnesses” are considered as otherwise unexplained symptoms that persist for at least 6 months following antibiotic treatment for either proven or presumed infection with Borrelia spp. that cause Lyme disease. Keywords applied to the literature search were deliberately broadly inclusive, followed by abstracts and full-text screening to remove irrelevant articles (Table C-1). While it is possible that some studies still may not be captured by these search terms, the committee believes this approach balanced efficiency with the retrieval of a sufficiently representative collection of the evidence base.
Abstract and Full-Text Screening
The results from the search were imported into the PICO Portal online software service and de-duplicated. Abstracts were screened for inclusion eligibility (Table C-2) through dual review (National Academies staff), with a third member of the study staff to adjudicate differences. During abstract screening, articles were sorted into one of three categories for full-text review (disease mechanism, treatment, diagnosis). The inclusion criteria for each of the three categories were applied for full text screening (Table C-3).
TABLE C-1 Keywords Used to Describe Lyme IACI for Title and Abstract Literature Search
| Initial literature search |
|
| Supplemental literature search |
|
NOTE: IACI = infection-associated chronic illnesses.
TABLE C-2 Inclusion and Exclusion Criteria for Abstracts Screening
| Category | Inclusion | Exclusion |
|---|---|---|
| Date |
|
|
| Location |
|
|
| Language |
|
|
| Study design |
|
|
| Publication type |
|
|
| Outcomes |
|
|
TABLE C-3 Inclusion and Exclusion Criteria for Full-Text Screening
| Category | Inclusion | Exclusion |
|---|---|---|
| Disease mechanisms |
|
|
| Treatment |
|
|
| Diagnosis |
|
|
NOTE: IACI = infection-associated chronic illnesses.
Data Extraction and Summary of Evidence
Select data variables from the included full text articles were obtained by dual extraction with two methodologists at PICO Portal and verified to resolve misalignments and ensure completeness by a senior methodologist from PICO Portal (Table C-4). A total of 1,579 records were obtained from the literature search and imported into the PICO Portal system. After the removal of 755 duplicates, 824 abstracts were screened for eligibility by two reviewers and one adjudicator. Of the 232 titles included for review, one article could not be retrieved and an additional 146 were excluded
upon screening to yield 85 full text articles. The committee reviewed the articles and extracted data for each of the three categories. Summary findings and conclusions drawn based on this scoping review are presented throughout the report.
TABLE C-4 Data Extraction for Each Full-Text Category
| Variable | Disease Mechanism | Treatment | Diagnosis |
|---|---|---|---|
| Study design | ✓ | ✓ | ✓ |
| Controls | ✓ | ✓ | ✓ |
| Blinding | Not required | ✓ | ✓ |
| Intervention tested | Not required | ✓ | ✓ |
| Sample size | ✓ | ✓ | ✓ |
| Outcomes | ✓ | ✓ | ✓ |
SCOPING REVIEW: FULL TEXT ARTICLES INCLUDED
TABLE C-5 Articles Included in Scoping Review
| Reference | Category |
|---|---|
| Aucott et al. (2013) | Mechanisms |
| Aucott et al. (2016) | Mechanisms |
| Aucott et al. (2022) | Mechanisms, Diagnosis |
| Bayer et al. (1996) | Diagnosis |
| Bouquet et al. (2017) | Mechanism |
| Bouquet et al. (2016) | Mechanism |
| Bransfield et al. (2020) | Diagnosis |
| Cameron (2008) | Treatment |
| Chandra et al. (2010) | Mechanism |
| Chandra et al. (2011) | Mechanism |
| Chung et al. (2023) | Mechanism |
| Citera et al. (2017) | Diagnosis |
| Clarke et al. (2021) | Mechanism |
| Clarke et al. (2022) | Mechanism |
| Coughlin et al. (2018) | Mechanism, Diagnosis |
| Coyle et al. (1994) | Diagnosis |
| D’Adamo et al. (2015) | Treatment |
| Dattwyler et al. (1988) | Mechanism, Diagnosis |
| Derderian and Otenbaker (2024) | Treatment |
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