Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses

Arnaboldi, Paul M, Becker, Jacqueline, Nath, Avindra, Coyle, Patricia K, Handel, Andrew, Sellati, Timothy J, Gomes-Solecki, Maria, Garcet, Sandra, Henderson, Marianne K, Mullins, Piper, Cowan, Elliot, McCombie, W Richard, Wellins, Anna-Marie, Allegretta, Mark, Bergquist, Jonas, Schutzer, Steven E (June 2026) Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses. Brain, 149 (6). pp. 1842-1859. ISSN 0006-8950

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Abstract

Infection-associated chronic illnesses (IACIs) encompass a spectrum of poorly understood syndromes often marked by significant neurologic and multisystem symptoms following an infectious event. This review focuses on several diseases representative of the IACI spectrum. These are post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). Their clinical and biological complexity, combined with a lack of clear diagnostic criteria and objective available laboratory biomarkers, makes them difficult to distinguish from conditions with overlapping features. This presents challenges for research studies, as well as diagnosis and clinical management. This diagnostic ambiguity, coupled with heterogeneous patient presentations, has led to challenges in research, including misclassification of study participants and inconsistent or irreproducible findings. Some PTLDS research exemplifies these issues, which also extend to other IACIs. To advance the field, we highlight key methodological refinements and approaches for studying IACIs, including rigorous participant selection, standardized sample collection protocols, and the use of appropriate control groups, including those with microbiologic proof of the initial infection when known and technologically feasible. We also address broader influences on research quality, such as stigma, historical neglect, and the urgency to find treatments, which have contributed to the proliferation of poorly controlled studies and questionable practices. Drawing lessons from past challenges, we propose a path forward grounded in fit-for-purpose methodological rigour to improve scientific understanding and support evidence-based therapeutic development for IACIs.

Item Type:	Paper
Subjects:	diseases & disorders > Bacterial Infections diseases & disorders diseases & disorders > Bacterial Infections > Lyme disease
CSHL Authors:	McCombie, W. Richard
Communities:	CSHL labs > McCombie lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 June 2026
Date Deposited:	12 Jun 2026 13:46
Last Modified:	12 Jun 2026 13:46
PMCID:	PMC13232051
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42221

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