Abstract
Background and purpose
Residual symptoms after treatment of Lyme disease, sometimes called post‐treatment Lyme disease symptoms (PTLDs), are a matter of ongoing controversy. To guide treatment recommendations, a systematic review was performed of the available literature on specific treatment for PTLDs.
Methods
A systematic literature search of MEDLINE and CENTRAL was performed. No restrictions on case definitions, study types or specific interventions were applied to enable a comprehensive overview of the available literature. Risk of bias was assessed using the Cochrane risk of bias tools for randomized controlled trials. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Outcomes of interest were quality of life, fatigue, depression and cognition as well as adverse events.
Results
After screening 1274 records, eight eligible randomized controlled trials were included. Heterogeneity was observed regarding inclusion criteria, intervention, length of treatment and outcome measures. For efficacy outcomes, results are presented narratively due to heterogeneity. Eligible studies show no statistically significant difference between antibiotics and placebo regarding quality of life, cognition and depression. Results for fatigue were inconsistent whilst studies with low risk of bias showed no statistically significant difference between antibiotics and placebo. Meta‐analysis of safety outcomes showed statistically significantly more adverse events for antibiotics compared to placebo.
Conclusions
Available literature on treatment of PTLDs is heterogeneous, but overall shows evidence of no effect of antibiotics regarding quality of life, depression, cognition and fatigue whilst showing more adverse events. Patients with suspected PTLDs should not be treated with antibiotics.
Keywords: fatigue, Lyme disease, Lyme neuroborreliosis, post‐treatment Lyme disease syndrome, systematic review
INTRODUCTION
In studies on interventions, the prognosis of early Lyme disease after antibiotic treatment is usually good and the rate of residual symptoms is low [1, 2]. However, some patients experience residual symptoms as well as unspecific symptoms like fatigue and cognitive impairment after Lyme disease. Depending on the severity of these symptoms and their functional impact, some authors refer to this incomplete resolution of symptoms after treatment of Lyme disease as post‐treatment Lyme disease symptoms (PTLDs) or post‐treatment Lyme disease syndrome (PTLDS) [3, 4, 5, 6].
To provide a framework for further research, a case definition of PTLDS was proposed [4, 5]. To fulfil criteria for PTLDS, patients are required to have a documented episode of Lyme disease, have received a recommended course of antibiotic therapy, with resolution or stabilization of the objective manifestations of Lyme disease, have non‐specific symptoms (persistent or relapsing) that started within 6 months of the Lyme disease diagnosis and lasted for at least 6 months after completion of antibiotic therapy, and have no other condition that explains the symptoms [5].
The origin of these symptoms remains a matter of emotive debate. A recent prospective study reports an increase of unspecific symptoms of 6% after an episode of Lyme disease compared with the general population [7]. An elaborated analysis of this cohort mainly identified cognitive‐behavioural variables, like negative illness perceptions and poorer physical and social functioning, as well as higher baseline scores for depression, anxiety, fatigue and pain as predictors of persistent symptoms [8]. These findings suggest that persistent unspecific symptoms may not be a specific effect of borrelial infection, but rather a response mainly driven by patient‐immanent cognitive‐behavioural factors regarding coping and self‐perception. Other authors suggest autoimmune mechanisms as causative factors for unspecific persistent symptoms [9, 10]. Other explanations of PTLDs are new conditions unrelated to Lyme disease, microbiome changes due to infection with Borrelia as due to effects of antibiotic treatment, or metabolome changes [5]. Several studies report that incidence of unspecific symptoms after Lyme disease is similar to the general population [2, 11, 12, 13, 14]. A subset of PTLDs could therefore be due to anchoring bias with no causal relationship to the preceding episode of Lyme disease [15]. The concept of PTLDS has gained new attention after the recent emergence of post‐infectious syndromes like post‐COVID syndrome [16].
Healthcare practitioners are confronted with patients with residual symptoms after treatment of Lyme disease and demands of specific treatments in clinical practice. Some authors suggest extended antibiotic treatment in patients with residual symptoms, even when signs of ongoing infection are absent [17]. Several reports on severe adverse events (SAEs) and even fatalities are reported for such treatments [18, 19, 20].
In this systematic review, the available literature was assessed regarding treatment of PTLDs. The aim of this review was to summarize the available evidence to provide evidence‐based guidance to healthcare practitioners faced with patients with residual or unspecific symptoms after Lyme disease.
This review is not intended to acknowledge or investigate certain concepts regarding the pathogenesis of PTLDs.
METHODS
Search strategy and eligibility criteria
The aim was to achieve a comprehensive assessment of the available literature. Two databases were searched at MEDLINE via Ovid (Ovid MEDLINE® and Epub Ahead of Print, In‐Process, In‐Data‐Review and other Non‐Indexed Citations and Daily 1946 to July 2023) and the Cochrane Central Register of Controlled Trials in July 2023 for eligible studies. The reference lists of included studies were reviewed for further eligible studies. To search sensitively, the search strategy contains a combination of subject headings and text words. The search strategy for MEDLINE is shown in Appendix S1.
To address controversy regarding the diagnosis of PTLDs as well as the wealth of literature, broad search criteria were applied with no restrictions on specific diagnostic criteria for PTLDs. To address the wealth of available literature on this controversial topic, no restrictions regarding study type or type of intervention were applied.
Studies were eligible for inclusion if they reported a control group (either another active treatment or placebo) and included five or more patients.
As PTLDs comprise a variety of symptoms, our primary outcomes of interest were patient‐reported outcomes, particularly quality of life, fatigue, cognition and depression. Secondary outcomes were adverse events (AEs) and SAEs. AEs and SAEs were considered as reported by the original authors.
Data extraction and analysis
One reviewer (RD) evaluated titles and abstracts to determine the eligibility of the studies regarding target population, intervention and study design and publication type. Each reference included at this first stage was then further evaluated for eligibility at full‐text stage. Data were extracted by one reviewer (RD) from the full texts of included studies and entered into Review Manager (RevMan 5.4). Data extraction and data handling were performed in analogy to a previously published review protocol regarding the treatment of Lyme neuroborreliosis [21].
The assessment of risk of bias in the randomized controlled trials (RCTs) was performed independently by two reviewers (RD and GT) according to the Cochrane risk of bias tool to align with the methodology of a previous systematic review on Lyme neuroborreliosis [22, 23, 24]. In the event of disagreement, consensus was achieved through discussion with all the review authors. As PTLDs represent a controversial topic, our systematic review relied on studies with adequate methodological rigour. Therefore, studies with a rating of high risk of bias in any item were not considered for further qualitative analysis. Patient‐reported outcomes like quality of life and fatigue were of particular interest in this review. Assessment of these outcomes by the respective patients are inherently subjective. However, the item blinding of outcome assessment of patient‐reported outcomes was regarded as having low risk of bias when patients were adequately blinded regarding their specific interventions. As reported symptoms associated with PTLDs show a broad spectrum, reported outcomes on quality of life, fatigue, depression and cognition after treatment were regarded as efficacy outcomes.
Risk for publication bias was addressed in our systematic review by ensuring a comprehensive search for eligible studies. Only a small number of studies were available, so funnel plots were not used. As only a small number of studies were found with substantial differences in population, intervention and outcome assessment, the data on efficacy outcomes was summarized descriptively, rather than undertaking meta‐analyses.
For safety outcomes, the estimation of treatment effects was based on a fixed effect model according to the Mantel–Haenszel method. Heterogeneity amongst studies was investigated by using the χ 2 and I 2 methods [25].
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence for each outcome [26].
RESULTS
The search identified 1274 records. After screening, 1226 records were excluded, and 48 full‐text articles were retrieved for detailed examination (Figure 1). Of these records, nine met our inclusion criteria and corresponded to eight individual studies. All included studies were RCTs. Characteristics of included studies are shown in Table 1.
FIGURE 1.
Study flow diagram.
TABLE 1.
Characteristics of included studies.
| Study | Sample size (n) | Inclusion criteria | Pretreatment | Intervention | Duration | Country |
|---|---|---|---|---|---|---|
| Fallon 2008 [31] | 37 |
|
At least 3 weeks ceftriaxone | Ceftriaxone vs. placebo | 10 weeks | USA |
| Sjöwall 2012 [30] | 15 |
|
Ceftriaxone or doxycycline for at least 10–14 days | Doxycycline vs. placebo | 3 weeks | Sweden |
| Berende 2016 [27] | 280 |
|
Antibiotic treatment for 30–40 days | Ceftriaxone for 2 weeks, followed by 12 weeks doxycycline vs. clarithromycin/hydroxychloroquine vs. placebo | 12 weeks | Netherlands |
| Kaplan 2003 [34] | 129 |
|
Previous antibiotic treatment, various durations | Ceftriaxone for 30 days, followed by doxycycline for 60 days vs. placebo IV for 30 days followed by placebo by mouth for 60 days | 90 days | USA |
| Klempner 2001 [32] | 107 |
|
Previous antibiotic treatment, various durations | Ceftriaxone for 30 days, followed by doxycycline for 60 days vs. placebo IV for 30 days followed by placebo by mouth for 60 days | 90 days | USA |
| Krupp 2003 [33] | 48 |
by positive ELISA and Western blot serology
|
Antibiotic treatment for at least 3 weeks | Ceftriaxone vs. placebo | 28 days | USA |
| Cameron 2008 [29] | 84 |
|
Previous antibiotic treatments, drug and duration not stated | Amoxicillin vs. placebo | 3 months | USA |
| Murray 2022 [28] | 29 |
|
Previous antibiotic treatments, drug and duration not stated | Kundalini yoga vs. waiting list | 8 weeks | Netherlands |
Abbreviations: CDC, Center of Disease Control and Prevention; ELISA, enzyme‐linked immunosorbent assay; EM, erythema migrans; IDSA, Infectious Diseases Society of America; Ig, immunoglobulin; IV, intravenous; LNB, Lyme neuroborreliosis.
Considerable heterogeneity existed regarding inclusion criteria, type of intervention, treatment duration, measured outcomes and methods of outcome assessment amongst the available literature. Combined estimates for efficacy outcomes were not justified due to heterogeneous study criteria as well as differences in reporting of the outcome measures.
Assessment of risk of bias in the included studies is shown in Figure S1. One study had low risk of bias in all assessed items [27]. Two studies had ratings of high risk of bias in several items [28, 29].
Murray et al. report a non‐pharmacological intervention on PTLDS [28]. In this study, assessment of risk of bias was high for the items allocation concealment (block randomization in an unblinded setting leads to a predictable allocation process), blinding of participants and personnel/blinding of outcome assessment, incomplete outcome data and other bias (considerable imbalances regarding measurements of the respective outcomes at baseline).
In Cameron [29], assessment of risk of bias was high for the items allocation concealment, incomplete outcome data and other bias (estimated sample size not met, considerable imbalances regarding measurements of the respective outcomes at baseline). These two studies were therefore not considered for further qualitative analysis.
Quality of life
Quality of life was reported in four studies [27, 30, 31, 32]. All studies measured quality of life using the 36‐item Short Form Health Survey scale. However, the outcome was reported differently amongst these studies. Two studies report measures at the end of the treatment period [27, 31], whereas two studies report proportions of patients with improved, unchanged or worsened scores [30, 32]. All four studies similarly report no statistically significant difference between antibiotic treatment and placebo regarding quality of life in PTLDs patients. GRADE assessment for the comparison of antibiotic treatment and placebo concerning quality of life is low due to indirectness and imprecision (Table 2).
TABLE 2.
GRADE evidence table for the comparison antibiotic treatment vs. placebo in PTLDS.
| Quality assessment | Results | Certainty | |||||||
|---|---|---|---|---|---|---|---|---|---|
| No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Antibiotics n | Placebo n | ||
| Fatigue (various scales) | |||||||||
| 3 | RCTs | Not serious | Serious a | Serious b | Serious c | 228 | 132 | In two RCTs (including one with low risk of bias) no statistically significant difference regarding fatigue. In one RCT lower fatigue with antibiotic treatment in one scale, no statistically significant difference in another scale | Very low |
| Depression (measured with Beck Depression Inventory) | |||||||||
| 2 | RCTs | Not serious | Not serious | Serious b | Serious c | 84 | 77 | No statistically significant difference regarding depression | Low |
| Quality of life (various scales) | |||||||||
| 4 | RCTs | Not serious | Not serious | Serious b | Serious c | 274 | 183 | No statistically significant difference regarding quality of life | Low |
| Cognition (various scales) | |||||||||
| 4 | RCTs | Not serious | Not serious | Serious b | Serious c | 292 | 197 | No statistically significant difference regarding cognition | Low |
Abbreviations: PTLDS, post‐treatment Lyme disease syndrome; RCT, randomized controlled trial.
Heterogeneity regarding direction of the outcome estimates.
Relevant differences regarding inclusion criteria, type and length of intervention, timing and assessment of outcomes.
Pooled analysis not feasible.
Cognition
Cognition was reported in four studies [27, 31, 33, 34]. Available studies used different neuropsychological test batteries to assess cognition. All four studies similarly report no statistically significant difference between antibiotic treatment and placebo in PTLDs patients regarding cognition at the latest reported time point. GRADE assessment for the comparison of antibiotic treatment and placebo concerning cognition is low due to indirectness and imprecision (Table 2).
Depression
Depression was reported in two studies [31, 34]. Depression was measured in both studies using the Beck Depression Inventory. Both studies similarly report no statistically significant difference between antibiotic treatment and placebo in PTLDs patients regarding depression. GRADE assessment for the comparison of antibiotic treatment and placebo concerning depression is low due to indirectness and imprecision (Table 2).
Fatigue
Fatigue was reported in three studies [27, 31, 33]. Different scales were used to assess fatigue in the available studies. Two studies report no statistically significant difference between antibiotics and placebo regarding fatigue in PTLDs patients [27, 31]. One study reports a statistically significant difference regarding fatigue in the 11‐item Fatigue Severity Scale favouring antibiotic treatment, but no statistically significant difference in a visual analogue scale of fatigue [33]. GRADE assessment for the comparison of antibiotic treatment and placebo concerning fatigue is very low due to inconsistency, indirectness and imprecision (Table 2).
Adverse events
Data on AEs and SAEs as defined and reported by the original authors could be extracted from four studies (Table 3). One study reported that rates of AEs were ‘similar’ between interventions but did not report exact estimates [33]. Data on AEs could be pooled in meta‐analysis from four studies. The rate of AEs was statistically significantly higher in patients treated with antibiotics compared to placebo (relative risk 1.47, 95% confidence interval 1.11–1.95, p = 0.007, I 2 = 0%; Figure 2). The rate of SAEs was not statistically significantly different between antibiotics and placebo (Figure S2). However, several SAEs were associated with the mode of application of the intervention (catheter‐associated sepsis, thrombosis) which could not have occurred if the patient had not been treated at all. GRADE assessment for the comparison of antibiotic treatment and placebo concerning AEs is low due to indirectness and imprecision. For SAEs, GRADE assessment is very low due to indirectness and imprecision (Table 4).
TABLE 3.
Safety outcomes as reported in individual studies.
| Study | Safety outcome | Intervention | |
|---|---|---|---|
| Placebo | Antibiotics | ||
| Berende 2016 [27] | Overall patients | 98 | 182 |
| Drug related AE | 34 (35%) | 84 (46%) | |
| 0 (0%) | 4 (4%) (gastrointestinal complaints, chest pain, traffic accident) | ||
| Fallon 2008 [31] | Overall patients | 14 | 23 |
| Treatment related AE | 1 (7%) | 6 (26%) | |
| Klempner 2001 [32] | Overall patients | 65 | 64 |
| Any AE | 11 (17%) | 16 (25%) | |
| Any SAE | 0 (0%) | 2 (3%) (pulmonary embolism, gastrointestinal bleeding) | |
| Krupp 2003 [33] | Overall patients | 22 | 26 |
| Any AE | ‘Similar’ | ||
| Any SAE | 3 (13%) (IV sepsis) | 1 (4%) (anaphylaxia) | |
| Sjöwall 2012 [30] | Overall patients | 15 | 15 |
| Any AE | 1 (7%) | 5 (33%) | |
| Any SAE | 0 (0%) | 0 (0%) | |
Abbreviations: AE, adverse event; IV, intravenous; SAE, serious adverse event.
FIGURE 2.
Forest plot for the comparison of antibiotics versus placebo for adverse events.
TABLE 4.
GRADE evidence table regarding safety outcomes for the comparison antibiotic treatment vs. placebo in PTLDs.
| Certainty assessment | No. of patients | Effect | Certainty | ||||||
|---|---|---|---|---|---|---|---|---|---|
| No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Antibiotics | Placebo | Relative risk (95% CI) | |
| Adverse events | |||||||||
| 4 | RCTs | Not serious | Not serious | Serious a | Serious b | 111/284 (39.1%) | 47/192 (24.5%) | RR 1.47 (1.11–1.95, p = 0.007) | Low |
| Serious adverse events | |||||||||
| 4 | RCTs | Not serious | Not serious | Serious a |
Very serious c |
7/289 (2.4%) | 3/202 (1.5%) | RR 1.51 (0.44–5.12, p = 0.51) | Very low |
Abbreviations: CI, confidence interval; PTLDs, post‐treatment Lyme disease symptoms; RCT, randomized controlled trial; RR, relative risk.
The bold value (RR) represents ‘relative risk’.
Relevant differences regarding inclusion criteria, type and length of intervention.
Limited sample size.
Limited sample size and limited event size.
DISCUSSION
To summarize the available evidence and to inform decision making for treatment for PTLDs, a comprehensive literature search was performed. Overall, eight RCTs could be included. After assessment of risk of bias, data on treatment of PTLDs could be extracted from six RCTs. As many aspects of PTLDs remain controversial, including a missing consented case definition, relevant heterogeneity was expected.
The literature regarding treatment of PTLDs is heterogeneous. Due to considerable differences in inclusion criteria, choice and length of interventions, differences in choice of outcomes and assessment of outcomes as well as different levels of risk of bias in included studies, no quantitative syntheses with meta‐analysis were performed. Different strains of Borrelia burgdorferi show different patterns of geographical distribution and are associated with a different spectrum of clinical manifestations of Lyme disease [15]. Four of the six eligible studies were conducted in North America; the results from this review may be less applicable to regions with different distributions of Borrelia strains, as in Europe. Patients with late Lyme disease, especially Lyme neuroborreliosis with affection of the central nervous system, show a higher amount of residual symptoms compared to early manifestations of Lyme disease [1, 13, 35]. Differential effects on different manifestations of Lyme disease could not be assessed due to absent reporting. Therefore, applicability of the results on residual symptoms after different manifestations of Lyme disease is limited.
However, results from included studies show consistency regarding the reported outcomes. Antibiotic treatment was not superior to placebo regarding quality of life, depression and cognition in PTLDs. Regarding fatigue, antibiotic treatment was not superior to placebo in two RCTs, one with low risk of bias and broad inclusion criteria [27]. Another study reported inconsistent results regarding fatigue [33]. The methodology from this study was previously criticized by other authors, especially discussing inconsistent results with differences in one scale of fatigue but no difference in another scale applied in the same study [36]. The overall effect on fatigue was furthermore marginal in patients with antibiotics and placebo alike and did not lead to an improvement in quality of life scales in included patients [36]. In the light of these issues, the available evidence does not point to an advantage for treatment with antibiotics regarding fatigue. Our results are in line with recommendations from several national guidelines [37, 38, 39].
A recent Chinese systematic review on treatment of PTLDs reports contradicting results to our review [40]. Zhang et al. published a network meta‐analysis on antibiotic treatment of PTLDs and reported a superior efficacy of ceftriaxone over doxycycline and placebo regarding fatigue. We challenge these findings for several reasons. First, the authors fail to include one recent study on antibiotic treatment of PTLDs [30]. Further methodological issues have to be discussed. The authors report a network meta‐analysis, which gives special attention to the comparability and homogeneity of the included studies [41]. However, the core assumption for network meta‐analysis of transitivity is not fulfilled, as relevant heterogeneity regarding target population, intervention, length of treatment and outcome measures is present in the included studies. Assessment of validity, methodological quality and especially risk of bias of the included studies was also not performed by Zhang et al., which are critical steps in performing a systematic review. The results of the review of Zhang et al. are therefore disputed.
Implications for research
Prospective studies on Lyme disease identified cognitive‐behavioural variables, like negative illness perceptions, as powerful predictors of persistent symptoms after treatment [8]. Further research should focus on how these cognitive‐behavioural risk factors of persistent symptoms could be assessed and addressed in the initial treatment of Lyme disease to possibly prevent persistent symptoms or support patients on how to cope with post‐infectious fatigue. Symptom‐specific interdisciplinary approaches regarding persistent symptoms may be promising in the management of patients with persistent symptoms after Lyme disease [42].
CONCLUSION
A summary is provided of the available evidence based on a comprehensive literature search, a systematic and structured assessment of risk of bias as well as an assessment of the certainty of the available evidence applying the GRADE approach.
Evidence from the available RCTs does not support a benefit of antibiotic treatment regarding efficacy. Furthermore, the available literature shows a statistically significantly higher rate of AEs with antibiotic treatment compared to placebo. Available RCTs show no statistically significant difference between antibiotics and placebo regarding SAEs. However, this finding is questionable due to the limited event size. SAEs and even fatalities after extended antibiotic treatment have been reported repeatedly [18, 19]. Aside from AEs, overuse of antibiotic treatment adds to the global crisis of emerging antibiotic resistance and should be avoided [43]. Antibiotic treatment should not be used in patients with PTLDs.
AUTHOR CONTRIBUTIONS
Rick Dersch: Conceptualization; writing – original draft; methodology; formal analysis; project administration; investigation. Gabriel Torbahn: Writing – review and editing; methodology; validation. Sebastian Rauer: Conceptualization; writing – review and editing; funding acquisition; supervision; project administration.
CONFLICT OF INTEREST STATEMENT
R.D. reports lecture fees from Bayer, Alexion, Argenx, Merck, Novartis, Roche and Sanofi and consulting fees from Pfizer. G.T. reports no conflicts of interest. S.R. reports receiving consulting and lecture fees, and grant and research support from Baxter, Bayer Vital GmbH, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi‐Aventis and Teva. Furthermore, S.R. is a founding executive board member of Ravo Diagnostika GmbH, which sells in vitro diagnostic medical devices for the detection of infectious diseases (including Lyme neuroborreliosis) and paraneoplastic autoantibodies.
Supporting information
Appendix S1.
Figure S1.
Figure S2.
ACKNOWLEDGEMENTs
Open Access funding enabled and organized by Projekt DEAL.
Dersch R, Torbahn G, Rauer S. Treatment of post‐treatment Lyme disease symptoms—a systematic review. Eur J Neurol. 2024;31:e16293. doi: 10.1111/ene.16293
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1.
Figure S1.
Figure S2.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.