Prevalence of persistent symptoms after treatment for lyme borreliosis: A prospective observational cohort study

Abstract

Background: Concerns about long-lasting symptoms attributed to Lyme borreliosis (LB) are widespread in the Western world, while such symptoms are highly prevalent in the general population.

Methods: In the largest prospective study to date, adults with physician-confirmed LB were included at the start of antibiotic treatment. Primary outcomes, prevalence of persistent symptoms and symptom severity, were assessed using three-monthly standardised questionnaires during one year. Persistent symptoms were defined as impaired scores for fatigue (CIS, subscale fatigue), cognitive impairment (CFQ) or pain (SF-36, subscale bodily pain) ≥6 months, with onset <6 months. Outcomes were compared with a longitudinal general population and a tick-bite cohort without LB as a reference.

Findings: Of 1135 LB patients (94•8% erythema migrans, 5•2% disseminated LB), 1084 fulfilled primary analysis criteria, as well as 1942 population and 1887 tick-bite controls. Overall prevalence of persistent symptoms in LB patients was 27•2% (95%CI, 24•7%-29•7%); 6•0% and 3•9% higher than in population (21•2%, 95%CI, 19•3%-23•1%; p < 0•0001) and tick-bite (23•3%, 95%CI 21•3%-25•3%; p = 0•016) cohorts, respectively. At 12 months, fatigue, cognitive impairment, and pain were significantly more severe in erythema migrans patients than in reference cohorts, while in disseminated LB patients, only pain was more severe.

Interpretation: In treated LB patients, persistent symptoms were significantly more prevalent and symptoms were more severe than in individuals without LB, although the background prevalence was substantial. This suggests an association, either direct or indirect, between persistent symptoms and LB in a relatively small subset of patients.

Funding: ZonMw; Dutch Ministry of Health, Welfare and Sport.

Keywords: ACA, Acrodermatitis chronica atrophicans; CFQ, Cognitive Failure Questionnaire; CIS, Checklist Individual Strength; EM, Erythema migrans; LB, Lyme borreliosis; PCR, Polymerase Chain Reaction; PHQ-15, Patient Health Questionnaire; PTLDS, Post-treatment Lyme Disease Syndrome; SF-36, SF-36 item Health Survey; TiC-P, Treatment Inventory of Costs in Patients with psychiatric disorders; s.l., sensu lato.

Fig. 1

Enrollment and follow-up *Of which 557 individuals were screened online (www.tekenradar.nl). ‘Tekenradar’ (www.tekenradar.nl) is an online platform where individuals can report tick bites and LB diagnoses. This website was used for both inclusion and follow-up (questionnaires). **Some participants were excluded for more than one reason. ^¶The sum of manifestations exceeds the number of included patients with Lyme borreliosis, as one patient was diagnosed with two concurrent manifestations. ^‡1 patient had two concurrent skin lesions, denoted as EM as inclusion criteria for multiple EM were not met. ^#According to the inclusion criteria as defined in Table S1. Abbreviations: CFQ = Cognitive Failure Questionnaire, CIS = Checklist Individual Strength, EM = erythema migrans, LB = Lyme borreliosis, SF-36 = SF-36 item Health Survey.

Fig. 2

Prevalence of persistent symptoms Standardised prevalence (with 95% confidence intervals) of participants with persistent symptoms per cohort, comparing all LB patients, as well as the subset of patients with EM or disseminated LB, with the population (1) and tick bite (2) cohorts, using the primary scenario for substitution of missing data. (A) Percentage of participants meeting the definition of persistent symptoms (i.e., having at least one persistent symptom). (B-D) Percentage of participants reporting each individual persistent symptom. Participants may have reported two or more symptoms, therefore the sum of the percentages does not equal the overall prevalence of persistent symptoms. * p ≤ 0•05; ** p ≤ 0•01; *** p ≤ 0•001; ns = not significant. P values are provided in Table S6. Abbreviations: EM = erythema migrans, LB = Lyme borreliosis.

Fig. 3

Symptom severity Standardised mean severity scores for the CIS (subscale fatigue), CFQ, and SF-36 (subscale bodily pain) at five time points, with 95% confidence intervals. CIS subscale fatigue scores range between 8 and 56, a higher score indicating more fatigue, and a norm score of <35. CFQ scores range from 0 to 100, a higher score indicating more impaired cognitive functioning, and a norm score of <44. Scores on the SF-36, subscale bodily pain, range between 0 and 100, a higher score indicating less pain, and a norm score of >55. Dashed lines indicate norm scores thresholds. (A-C) Mean scores for LB patients with EM or disseminated LB, and the population and tick bite cohorts. (D-F) Mean scores for all LB patients who meet the definition of persistent symptoms and those who did not meet the definition of persistent symptoms. Abbreviations: CFQ = Cognitive Failure Questionnaire, CIS = Checklist Individual Strength, EM = erythema migrans, LB = Lyme borreliosis, SF-36 = SF-36 item Health Survey.

Fig. 4

Prevalence of impaired questionnaire scores at each time point Standardised prevalence of reported symptoms (with 95% confidence intervals), based on available impaired questionnaire scores, on each time point per cohort, for fatigue (A), cognitive impairment (B), and pain (C). Abbreviations: EM = erythema migrans, LB = Lyme borreliosis.