Determinants of persistent symptoms after treatment for Lyme borreliosis: a prospective observational cohort study

Hedwig D Vrijmoeth; Jeanine Ursinus; Margriet G Harms; Anna D Tulen; M E Baarsma; Freek R van de Schoor; Stefanie A Gauw; Tizza P Zomer; Yolande M Vermeeren; José A Ferreira; Hein Sprong; Kristin Kremer; Hans Knoop; Leo A B Joosten; Bart Jan Kullberg; Joppe W Hovius; Cees C van den Wijngaard

doi:10.1016/j.ebiom.2023.104825

Determinants of persistent symptoms after treatment for Lyme borreliosis: a prospective observational cohort study

EBioMedicine. 2023 Dec:98:104825. doi: 10.1016/j.ebiom.2023.104825. Epub 2023 Nov 27.

Authors

Hedwig D Vrijmoeth¹, Jeanine Ursinus², Margriet G Harms³, Anna D Tulen³, M E Baarsma², Freek R van de Schoor¹, Stefanie A Gauw², Tizza P Zomer⁴, Yolande M Vermeeren⁴, José A Ferreira³, Hein Sprong³, Kristin Kremer³, Hans Knoop⁵, Leo A B Joosten¹, Bart Jan Kullberg¹, Joppe W Hovius², Cees C van den Wijngaard⁶

Affiliations

¹ Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
² Department of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC, Location AMC, University of Amsterdam, P.O. Box 22660, 1100 DD, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands.
³ National Institute for Public Health and Environment (RIVM), Center for Infectious Disease Control, P.O. Box 1, 3720 BA, Bilthoven, the Netherlands.
⁴ Lyme Center Apeldoorn, Gelre Hospital, P.O. Box 9014, 7300 DS, Apeldoorn, the Netherlands.
⁵ Department of Medical Psychology, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, P.O. Box 22660, 1100 DD, Amsterdam, the Netherlands.
⁶ National Institute for Public Health and Environment (RIVM), Center for Infectious Disease Control, P.O. Box 1, 3720 BA, Bilthoven, the Netherlands. Electronic address: kees.van.den.wijngaard@rivm.nl.

Abstract

Background: Patients treated for Lyme borreliosis (LB) frequently report persistent symptoms. Little is known about risk factors and etiology.

Methods: In a prospective observational cohort study with a follow-up of one year, we assessed a range of microbiological, immunological, genetic, clinical, functional, epidemiological, psychosocial and cognitive-behavioral variables as determinants of persistent symptoms after treatment for LB. Between 2015 and 2018 we included 1135 physician-confirmed LB patients at initiation of antibiotic therapy, through clinical LB centers and online self-registration. Two reference cohorts of individuals without LB (n = 4000 and n = 2405) served as a control. Prediction analyses and association studies were used to identify determinants, as collected from online questionnaires (three-monthly) and laboratory tests (twice).

Findings: Main predictors of persistent symptoms were baseline poorer physical and social functioning, higher depression and anxiety scores, more negative illness perceptions, comorbidity, as well as fatigue, cognitive impairment, and pain in 295 patients with persistent symptoms. The primary prediction model correctly indicated persistent symptoms in 71.0% of predictions (AUC 0.79). In patients with symptoms at baseline, cognitive-behavioral responses to symptoms predicted symptom persistence. Of various microbiological, immunological and genetic factors, only lower IL-10 concentrations in ex vivo stimulation experiments were associated with persistent symptoms. Clinical LB characteristics did not contribute to the prediction of persistent symptoms.

Interpretation: Determinants of persistent symptoms after LB were mainly generic, including baseline functioning, symptoms and cognitive-behavioral responses. A potential role of host immune responses remains to be investigated.

Funding: Netherlands Organisation for Health Research and Development (ZonMw); the Dutch Ministry of Health, Welfare and Sport (VWS).

Keywords: Erythema migrans; Lyme borreliosis; Persistent symptoms.

Publication types

Observational Study

MeSH terms

Anti-Bacterial Agents / therapeutic use
Humans
Lyme Disease* / diagnosis
Lyme Disease* / drug therapy
Lyme Disease* / epidemiology
Netherlands
Prospective Studies
Surveys and Questionnaires

Substances

Anti-Bacterial Agents