Proposed Research Classification Criteria for Lyme Disease in Infection Associated Chronic Illness Studies

Brian Anthony Fallon ^1* Mara Kuvaldina ¹ Nevena Zubcevik ² Roberta Debiasi ³ Sarah Mulkey ³ Charles Chiu ⁴ Felicia Chow ⁵ Kristopher Paolino ⁶ Randy Lai ¹ David Putrino ⁷ Amy Proal ⁸ Martina Pavlicova ⁹ John Aucott ¹⁰

• ¹ Columbia University Irving Medical Center, Columbia University, New York, United States
• ² Invisible International, Towson, Maryland, United States
• ³ Children’s Research Institute, Children’s National Hospital, Washington DC, District of Columbia, United States
• ⁴ Department of Medicine, School of Medicine, University of California San Francisco, San Francisco, California, United States
• ⁵ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, United States
• ⁶ Institute for Global Health and Translational Science, Upstate Medical University, Syracuse, New York, United States
• ⁷ Mount Sinai Health System, New York, New York, United States
• ⁸ Polybio Research Foundation, Medford, Massachusetts, United States
• ⁹ Mailman School of Public Health, Columbia University, New York City, New York, United States
• ¹⁰ Division of Rheumatology, Department of Medicine, School of Medicine, Johns Hopkins Medicine, Baltimore, Maryland, United States

Background. Research on patients with persistent symptoms despite prior treatment for Lyme disease can be challenging to interpret given the diversity of criteria selected to characterize Lyme disease and to define the syndrome of those with persistent symptoms. Because most research studies only include patients with well-documented prior Lyme disease, the generalizability of the study results is limited, excluding the larger group of patients often seen in community practice who do not meet these stringent enrollment criteria. Researchers at the Lyme and other Tick-borne Diseases Clinical Trials Network (LTD-CTN) recognized early on that a research classification system was needed to facilitate the design of studies that are more inclusive. This paper presents a proposed research classification system.Methods. Criteria used in published clinical research on previously treated Lyme disease were reviewed. Clinical expertise was provided by principal investigators in the LTD-CTN. Further input was obtained from a diverse panel of stakeholders in the field, including clinicians, academic researchers, and patient advocates. This classification system was developed based on feedback collected from all these sources.Results. The new research classification system proposes criteria for Lyme disease at different levels of diagnostic certainty: definite, probable, possible, and uncertain. Criteria for ascertainment for each classification level and additional factors to be considered in patient selection for research are described.The proposed research classification system should improve the quality and generalizability of clinical research by providing clear case definitions for enrollment of a more diverse group of patients with sequelae from Lyme disease.