Post-treatment Lyme Disease Research Articles

Autoantibodies in post-treatment Lyme disease and association with clinical symptoms.

Autoantibodies have been described in the post-infectious state, specifically after Lyme disease and COVID-19. We aimed to describe the prevalence and potential clinical utility of several commercially available autoantibodies after these infections. Euroimmun panels (myositis, scleroderma and ANA5) were assayed using sera from patients with Lyme disease with return to health (RTH) (n=70), post-treatment Lyme disease (n=58), COVID-19 RTH (n=47) and post-acute symptoms of COVID-19 (n=22). The post-Lyme questionnaire of symptoms (PLQS) was used to determine symptom burden after Lyme disease. There was no statistically significant difference in autoantibody prevalence across the four groups (p=0.746). A total of 21 different antibodies were found in the Lyme cohorts and 8 different antibodies in the COVID-19 cohorts. The prevalence of scleroderma-associated antibodies was higher after Lyme disease than COVID-19 (12.5% vs. 2.9%, p=0.026). There was no statistically significant difference in symptom burden based on antibody status. Several autoantibodies were found after Borrelia burgdorferi and SARS-CoV2 infection, although the prevalence was similar in those with persistent symptoms and those who returned to health. While our data show no difference in autoantibody prevalence across the four post-infectious states, we do not imply that autoantibodies are irrelevant in this setting. Rather, this study highlights the need for novel antibody discovery in larger cohorts of well-defined patient populations.

Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and comparison of pathogenesis.

Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977. It is well-documented that about 10% of patients properly treated with antibiotics never fully recover, but instead go on to develop a chronic illness dubbed, posttreatment Lyme disease syndrome (PTLDS) characterized by severe fatigue, cognitive slowing, chronic pain, and sleep difficulties. This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome (ME/CFS), a strikingly similar syndrome. In the majority of the PTLDS studies, at least four of the six major symptoms of ME/CFS were also noted, including substantial impairment in activity level and fatigue for more than 6 months, post-exertional malaise, and unrefreshing sleep. In one of the included PTLDS articles, 26 of the 29 ME/CFS symptoms were noted. This study adds to the expanding literature on the post-active phase of infection syndromes, which suggests that chronic illnesses such asPTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Does Biological Sex Matter in Lyme Disease? The Need for Sex-Disaggregated Data in Persistent Illness.

Biological sex should be included as an important variable in clinical research studies to identify outcome differences between men and women. Very few Lyme disease studies were designed to consider sex-based differences or gender bias as an important component of the research design. To assess sex-based differences in Lyme disease patients who were clinically diagnosed and reported remaining ill for six or more months after receiving antibiotic treatment, we analyzed self-reported clinical data from 2170 patients in the MyLymeData patient registry. We also reviewed previous Lyme disease studies for distribution of patients by biological sex according to stage of illness, data source, and definition of disease used as enrollment criteria. In MyLymeData, women reported more tick-borne coinfections, worse symptoms, longer diagnostic delays, more misdiagnoses, and worse functional impairment than men. No differences were reported in antibiotic treatment response or side effects. In our review, of clinical research trials and data sources, we identified a smaller percentage of women in studies of acute Lyme disease and a larger percentage of women in studies of persistent illness. Samples and data sources that were more reflective of patients seen in clinical practice had a higher percentage of women than randomized controlled trials and post-treatment Lyme disease studies. Our results indicate that biological sex should be integrated into Lyme disease research as a distinct variable. Future Lyme disease studies should include sex-based disaggregated data to illuminate differences that may exist between men and women with persistent illness.

Lyme disease and the pursuit of a clinical cure.

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne illness in the United States. Many aspects of the disease are still topics of controversy within the scientific and medical communities. One particular point of debate is the etiology behind antibiotic treatment failure of a significant portion (10-30%) of Lyme disease patients. The condition in which patients with Lyme disease continue to experience a variety of symptoms months to years after the recommended antibiotic treatment is most recently referred to in the literature as post treatment Lyme disease syndrome (PTLDS) or just simply post treatment Lyme disease (PTLD). The most commonly proposed mechanisms behind treatment failure include host autoimmune responses, long-term sequelae from the initial Borrelia infection, and persistence of the spirochete. The aims of this review will focus on the in vitro, in vivo, and clinical evidence that either validates or challenges these mechanisms, particularly with regard to the role of the immune response in disease and resolution of the infection. Next generation treatments and research into identifying biomarkers to predict treatment responses and outcomes for Lyme disease patients are also discussed. It is essential that definitions and guidelines for Lyme disease evolve with the research to translate diagnostic and therapeutic advances to patient care.

Single-cell sequencing of PBMC characterizes a distinct inflammatory monocyte subset in Lyme disease patients with Post-Treatment Lyme Disease Syndrome (PTLD)

Abstract Lyme disease (LD) is the most common tick-borne disease in the United States. Most LD patients can return to healthy (RTH) status after antibiotic treatment. Still, 20% of LD patients develop Post-Treatment Lyme Disease Syndrome (PTLD), including fatigue and musculoskeletal pain that persist for a long time. Previous RNA-seq studies showed that most individuals with PTLD had an inflammatory gene expression compared to RTH, but the specific immune components that contribute to PTLD are not well understood. Here, we performed the single-cell sequencing analysis of PBMCs from 6 RTH and 4 PTLD patients collected during multiple clinic visits after antibiotic treatment over two years. We identified a CD14+ monocyte cluster significantly enriched in 4/4 PTLD patients and 2/6 RTH patients from the beginning to 6 months post-treatment. This monocyte cluster displayed distinct inflammatory gene signatures such as CCL3, CCL4, IL1B, CXCL2, CXCL8, and others. RTH patients with such inflammatory monocytes showed low expression of CXCR2 compared to PTLD, suggesting that higher CXCR2 signaling in inflammatory monocytes may contribute to the development of PTLD. In addition, pathway analysis of upregulated genes in PTLD inflammatory monocytes indicated that this subset was induced by molecules of bacterial origin and involved in the regulation of lymphocyte activation. In conclusion, our single-cell study identified a distinct inflammatory monocyte that was enriched and may contribute to PTLD. Tracking this inflammatory monocyte subset could lead to a more accurate prediction of PTLD and identify molecular biomarkers and pathways for therapeutic intervention.

Systematic comparisons between Lyme disease and post-treatment Lyme disease syndrome in the U.S. with administrative claims data.

Post-treatment Lyme disease syndrome (PTLDS) is used to describe Lyme disease patients who have the infection cleared by antibiotic but then experienced persisting symptoms of pain, fatigue, or cognitive impairment. Currently, little is known about the cause or epidemiology of PTLDS. We conducted a data-driven study with a large nationwide administrative dataset, which consists of more than 98 billion billing and 1.4 billion prescription records between 2008 and 2016, to identify unique aspects of PTLDS that could have diagnostic and etiologic values. We defined PTLDS based on its symptomatology and compared the demographic, longitudinal changes of comorbidity, and antibiotic prescriptions between patients who have Lyme with absence of prolonged symptoms (APS) and PTLDS. The age and temporal distributions were similar between Lyme APS and PTLDS. The PTLDS-to-Lyme APS case ratio was 3.42%. The co-occurrence of 3 out of 19 chronic conditions were significantly higher in PTLDS versus Lyme APS-odds ratio and 95% CI for anemia, hyperlipidemia, and osteoarthrosis were 1.46 (1.11-1.92), 1.39 (1.15-1.68), and 1.62 (1.23-2.12) respectively. We did not find significant differences between PTLDS and Lyme APS for the number of types of antibiotics prescribed (incidence rate ratio=1.009, p=0.90) and for the prescription of each of the five antibiotics (FDR adjusted p values 0.72-0.95). PTLDS cases have more codes corresponding to anemia, hyperlipidemia, and osteoarthrosis compared to Lyme APS. Our finding of hyperlipidemia is consistent with a dysregulation of fat metabolism reported by other researchers, and further investigation should be conducted to understand the potential biological relationship between the two. Steven & Alexandra Cohen Foundation, Global Lyme Alliance, and the Pazala Foundation; National Institutes of Health R01ES032470.

Pediatric Lyme disease: systematic assessment of post-treatment symptoms and quality of life.

Lyme disease is common among children and adolescents. Antibiotic treatment is effective, yet some patients report persistent symptoms following treatment, with or without functional impairment. This study characterized long-term outcome of pediatric patients with Lyme disease and evaluated the case definition of post-treatment Lyme disease (PTLD) syndrome. The sample included 102 children with confirmed Lyme disease diagnosed 6 months-10 years prior to enrollment (M = 2.0 years). Lyme diagnosis and treatment information was extracted from the electronic health record; parent report identified presence, duration, and impact of symptoms after treatment. Participants completed validated questionnaires assessing health-related quality of life, physical mobility, fatigue, pain, and cognitive impact. Most parents reported their child's symptoms resolved completely, although time to full resolution varied. Twenty-two parents (22%) indicated their child had at least one persistent symptom >6 months post-treatment, 13 without functional impairment (PTLD symptoms) and 9 with functional impairment (PTLD syndrome). Children with PTLD syndrome had lower parent-reported Physical Summary scores and greater likelihood of elevated fatigue. In the current study, most children with Lyme disease experienced full resolution of symptoms, including those who initially met PTLD syndrome criteria. Effective communication about recovery rates and common symptoms that may persist post-treatment is needed. The majority of pediatric patients treated for all stages of Lyme disease reported full resolution of symptoms within 6 months. 22% of pediatric patients reported one or more symptom persisting >6 months, 9% with and 13% without accompanying functional impairment. Effective communication with families about recovery rates and common symptoms that may persist post-treatment of Lyme disease is needed.

Neuroborreliosis and Post-Treatment Lyme Disease Syndrome: Focus on Children.

Neuroborreliosis is a form of Lyme Borreliosis (LB) that affects various structures of the central and peripheral nervous system. Although most cases of LB can be cured with a course of antibiotics, some children can present prolonged symptoms, which may constitute post-treatment Lyme disease syndrome (PTLDS). The aim of our analysis was the long-term observation of children with NB and the determination of their risk of PTLDS. The clinical observation was supplemented by a laboratory study based on the assessment of the dynamics of anti-VlsE (variable major protein-like sequence, expressed) IgG antibodies in children with NB after antibiotic therapy. The prospective survey based on 40 children presented 1-2 forms of NB. The control group consisted of 36 patients with analogical symptoms for whom LB was excluded. Our long-term observation showed a low risk of developing long-term complications in children who received antibiotic therapy in accordance with the recommendations. The concentration of anti-VlsE IgG demonstrates a statistical significance for differences between the control and the study groups for each measurement period. Higher values of anti-VlsE IgG were observed in the study group, and the concentration decreased from the first measurement period to the next. The article emphasizes the importance of the long-term follow-up of children with neuroborreliosis.

Cost of illness in patients with post-treatment Lyme disease syndrome in Belgium.

A proportion of patients with Lyme borreliosis (LB) report long-term persisting signs and symptoms, even after recommended antibiotic treatment, which is termed post-treatment Lyme disease syndrome (PTLDS). Consensus on guidance regarding diagnosis and treatment is currently lacking. Consequently, patients suffer and are left searching for answers, negatively impacting their quality of life and healthcare expenditure. Yet, health economic data on PTLDS remain scarce. The aim of this article is therefore to assess the cost-of-illness related to PTLDS, including the patient perspective. PTLDS patients (N = 187) with confirmed diagnosis of LB were recruited by a patient organization. Patients completed a self-reported questionnaire on LB-related healthcare utilization, absence from work and unemployment. Unit costs (reference year 2018) were obtained from national databases and published literature. Mean costs and uncertainty intervals were calculated via bootstrapping. Data were extrapolated to the Belgian population. Generalized linear models were used to determine associated covariates with total direct costs and out-of-pocket expenditures. Mean annual direct costs amounted to €4618 (95% CI €4070-5152), of which 49.5% were out-of-pocket expenditures. Mean annual indirect costs amounted to €36081 (€31312-40923). Direct and indirect costs at the population level were estimated at €19.4 and 151.5 million, respectively. A sickness or disability benefit as source of income was associated with higher direct and out-of-pocket costs. The economic burden associated with PTLDS on patients and society is substantial, with patients consuming large amounts of non-reimbursed healthcare resources. Guidance on adequate diagnosis and treatment of PTLDS is needed.

Myositis Autoantibodies in Patients with Suspected Post-Treatment Lyme Disease Syndrome.

Most patients suffering from Lyme disease are effectively treated with antibiotics. In some patients, however, problems persist for a long time despite appropriate therapy. The term post-treatment Lyme disease syndrome (PTLDS) is currently used for this condition in scientific literature. The pathogenesis is still not precisely known, but the involvement of immunopathological mechanisms is assumed. In our study, we analyzed the presence of autoantibodies including myositis-specific (MSA) and myositis-associated autoantibodies (MAA) in patients with laboratory proven history of Lyme disease and with clinical symptoms of PTLDS. A total of 59 patients meeting the criteria for PTLDS were enrolled in this study. The control group consisted of 40 patients undergoing differential diagnosis of neurological disorders without clinical and/or laboratory-proven history of Lyme disease. The presence of autoantibodies was determined by immunoblot methods and positive samples were further tested for serum creatine kinase (CK) and myoglobin levels. The presence of myositis autoantibodies was detected in 18 subjects with suspected PTLDS (30.5%), but only in 5% of control subjects exhibiting no evidence of Lyme disease history. The difference was statistically significant (p = 0.002). The subsequent biochemical analysis of muscle-damage markers in positive subjects found a mild elevation in six MSA/MAA-positive PTLDS patients. The study detected raised MSA/MAA autoantibodies formation in the group of PTLDS patients raising the question about their involvement in the pathogenesis of this syndrome.

Efficacy and safety of antibiotic therapy for post-Lyme disease? A systematic review and network meta-analysis

BackgroundAt present, the pathogenesis of post-treatment Lyme disease (PTLDS) is not clear, so the treatment scheme of PTLDS, especially antibiotic treatment, is still controversial. This study aims to evaluate the efficacy of antibiotics in the treatment of PTLDS using network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, a systematic literature search was conducted on randomized controlled trials in PubMed, EMBASE, Web of Science and Cochrane Library (the literature was published from database inception through December 16, 2022). Using random effect model and fixed effect model. STATA17.0 software was used to evaluate the quality and heterogeneity of the included research literature.ResultsThe system included 4 randomized controlled trials (485 subjects). The network meta-analysis showed that ceftriaxone had better results than placebo [Mean = 0.87, 95% CI (0.02, 1.71)] and doxycycline [Mean = 1.01, 95% CI (0.03, 1.98)] in FSS scale scores. There was no statistical difference in FSS scale scores of other drugs after treatment. In terms of FSS score results, Ceftriaxone was the best intervention according to the SUCRA value of each treatment (97.7). The analysis of outcome indicators such as Beck Depression Inventory (BDI), Mental-health Scale and Physical-functioning scale showed that there was no statistically significant difference between the antibiotic group and placebo group.ConclusionCeftriaxone treatment may be the best choice for antibiotic treatment of PTLD, which provides useful guidance for antibiotic treatment of PTLD in the future.

High dose intravenous vitamin C for lyme disease: a safety and tolerability study with an exploratory assessment of treatment efficacy.

Lyme disease is the most common vector-borne disease in the United States with an estimated 476,000 new cases per year. Delays in diagnosis and treatment are common and there is a lack of consensus on the antibiotic therapy protocols to ensure successful outcomes. Much of this discord is due to the observation that more than 50 percent of people treated with conventional antibiotic protocols, which have changed little in the last 30 years, report persistent and/or recurring symptoms within 6 months of completing treatment. Labeled as chronic Lyme or post-treatment Lyme disease, it is a syndrome that afflicts more than 2 million people in the United States and can have a devastating impact on both quality of life and socioeconomic capacity. Despite these known treatment failures, the research community has lacked the funding necessary to advance our understanding of this syndrome or to explore innovative options to improve success. In this regard, complementary and alternative therapies, which are generally not patentable and have little potential for producing large economic gain, are generally disregarded in favor of new designer drugs or old reworked protocols. Intravenous vitamin C is one such example that has research validated effectiveness for a wide range of clinical conditions ranging from infection to cancer care. Achieving serum levels much higher than could be obtained orally, high dose intravenous vitamin C has the capacity to generate a concentration of intracellular peroxide that exerts both cytotoxic and immune stimulating effects. Unfortunately, these high doses of intravenous vitamin C have never been evaluated to establish safety and tolerability in Lyme positive patients. This study’s primary aim is to examine this question with the unique additions of DMSO and calcium EDTA into the formula to enhance tissue penetration and address biofilm formation respectively, both of which are known barriers to antibiotic success. The secondary aim of the study is to determine whether subjects gain relief from Lyme-associated symptoms by tracking changes in both the PROMIS-29 and the Horowitz-Lyme-MSIDS questionnaires. The exploratory objective is to assess changes in Lyme specific labs including the standard immunoblot and the T-cell based Elispot as well as the CD57+ lymphocyte immune marker. Administered at a 75-gram dose twice weekly over 12 weeks, high dose intravenous vitamin C was shown to be both well tolerated and safe. The secondary and exploratory aims of the study provide insight into the potential efficacy of this protocol, as both subjective measures of symptom severity and objective assessment of Lyme biomarkers showed marked improvement. Ultimately, this study paves the way for future research using high dose intravenous vitamin C in Lyme patents either as a stand-alone treatment or in synergy with other therapies. It is this author’s hope that employing an integrative medical approach such as this will eventually see chronic Lyme disease as a rare rather than common occurrence.

Borrelia Burgdorferi Sensu Lato Infection-induced Autoimmunity – A Decennary Literature Review

Abstract Borrelia burgdorferi sensu lato is a Gram-negative spirochete that causes Lyme disease (Lyme borreliosis). The signs and symptoms of Lyme disease are a consequence of the immune response to spirochete in soft tissues, and it is debated if said immune response can become an autoimmune disease of the body over time due to bacterial and HLA/MHC molecular mimicry. Continual Lyme Disease (CDL) also known as Post-Treatment Lyme Disease Syndrome (PTLDS) is a broad group of rapidly appearing flu-rash symptoms and cognitive difficulties combined with chronic fatigue that is observed after at least six months after completing treatment. This review contains scientific collections throughout the last 10 years of studies related to alleged post-infection auto-immunogenicity.

Language Fluency Deficits in Post-treatment Lyme Disease Syndrome.

Recent neurocognitive studies of patients with post-treatment Lyme disease syndrome (PTLDS) find consistent deficits in memory and processing speed. Language fluency deficits are observed as well but may be secondary to poor memory and slowing rather than an independent deficit. This study performed a secondary analysis of data presented previously, including individuals with PTLDS and comparison samples of healthy volunteers (HC) and patients with major depressive disorder (MDD), to determine if language fluency deficits could be accounted for by poor performance in these other neurocognitive domains. Basic verbal abilities, memory, and processing speed were all significantly associated with fluency performance. MDD patients' fluency deficits relative to HC were accounted for by these covariates. However, PTLDS patients' poorer fluency performance relative to both other groups was not. Language fluency appears to be an independent area of neurocognitive deficit within the constellation of PTLDS symptoms.

1362. Lyme Disease and Neurologic Manifestations in a District Hospital in Portugal

Abstract Background Lyme disease (LD), caused by Borrelia burgdorferi sensu lato’s species, has a wide presentation and severity and is often a neglected diagnosis. Neuroborreliosis (NB) occurs in 10-15% of patients (pts). This study evaluate NB (clinical manifestations, treatment and evolution) in a district acute hospital in Portugal. Methods Pts with Borrelia burgdorferi antibodies detected by ELISA, confirmed by Immunoblot and with neurological manifestations, between January 2015 - April 2022, in Pedro Hispano Hospital, Matosinhos, Portugal. Results Twenty-one pts: encephalitis (n=5), optic neuropathy (n=5), peripheral neuropathy (n=5), VII cranial nerve palsy (n=4), meningitis (n=3), myelitis (n=2), III cranial nerve palsy (n=1), meningoradiculitis (n=1), radiculitis (n=1) and stroke (n=1); majority female (71.4%) with mean age 50.8 years old. No cases of erythema migrans or arthralgias were observed. ECG performed in 13 pts and only one intraventricular conduction block detected. Lumbar puncture performed in 15 pts, only two presented inflammatory cerebrospinal fluid. Therapeutic strategies: 28 (n=4), 21 (n=5), 14 (n=3) and 10 (n=1) days of ceftriaxone and 28 (n=4), 21 (n=2) and 14 (n=2) days of doxycycline were applied. Complete clinical resolution observed in 6 pts (28.6%) and clinical improvement in 10 (47.6%). One (4.8%) developed post-treatment Lyme disease syndrome and one death occurred, not related with LD. Three pts had no clinical improvement but there was not disease progression, two treated with doxycycline (28 days) and the other one with ceftriaxone (21 days). Conclusion These data show the non-negligible prevalence of NB and the variability of clinical presentations that requires a high suspicion in the differential diagnosis. The heterogeneity of therapeutic regimens reflects the absence of a well-defined treatment and opens this discussion. Disclosures All Authors: No reported disclosures.

Lyme borreliosis in Belgium: a cost-of-illness analysis

BackgroundLyme borreliosis (LB) is the most common tick-borne disease in Europe and North America, yet its economic burden remains largely unknown. This study aimed to estimate the economic cost associated with the different clinical manifestations of LB in Belgium.MethodsAn incidence approach and societal perspective were used to estimate the total cost-of-illness for LB in Belgium. Costs were calculated for patients with erythema migrans (EM) or disseminated/late LB, including patients who developed post-treatment Lyme disease syndrome (PTLDS). Direct medical, direct non-medical (transportation & paid help) and indirect non-medical costs (productivity losses) were included in the analysis. Ambulatory cost data were collected through a prospective cohort study from June 2016 to March 2020, in which patients with LB were followed up 6 to 12 months after diagnosis. Hospitalization costs were retrieved from the Minimal Clinical Data registry, a mandatory registry for all Belgian hospitals, linked to the Minimal Financial Data registry. Costs were expressed in 2019 euros.ResultsThe total annual cost associated with clinical manifestations of LB in Belgium was estimated at €5.59 million (95% UI 3.82–7.98). Of these, €3.44 million (95% UI 2.05–5.48) or 62% was related to disseminated/late LB diagnoses and €2.15 million (95% UI 1.30–3.26) to EM. In general, direct medical costs and productivity losses accounted for 49.8% and 46.4% of the total costs, respectively, while direct non-medical costs accounted for only 3.8%. The estimated mean costs were €193 per EM patient and €5,148 per disseminated/late LB patient. While patients with PTLDS seemed to have somewhat higher costs compared to patients without PTLDS, the number of patients was too small to have representative estimates.ConclusionsWe estimate the total annual direct medical costs, direct non-medical and indirect non-medical costs associated with LB to exceed €5.5 million per year, almost evenly distributed between EM (40%) and disseminated/late LB (60%). EM costs 26 times less per patient but occurs also 16 times more frequently than disseminated/late LB. The cost burden remains limited by comparison to other infectious diseases due to the relative lower incidence.

Protein biomarker profiles in serum and CSF in 158 patients with PTLDS or persistent symptoms after presumed tick-bite exposure compared to those in patients with confirmed acute neuroborreliosis.

Current diagnostics for patients with lingering symptoms categorized as post-treatment Lyme disease syndrome (PTLDS) have their limitations and may be difficult to interpret. The aim of this exploratory study was to evaluate the feasibility of protein biomarker profiling as a diagnostic platform for this category of patients and to compare these results with similarly obtained results from a group of patients with acute neuroborreliosis. Two groups of patient cohorts (Cohort 1 and 2) were analyzed for biomarkers in serum and cerebrospinal fluid (CSF); the results were used for group-level comparison. Cohort 1 comprised 158 adult patients selected from 224 previously diagnosed patients, who between October 2015 and December 2018, after referral, were enrolled and structurally investigated based on defined inclusion criteria. They displayed similar lingering symptoms, with a duration of at least 6 months, after presumed previous tick-borne infection (TBI) and are fully described in a previously published study originating from the Center for Vector-borne Infections (CVI), Uppsala University Hospital, Sweden. Cohort 2, comprised 30 patients diagnosed at Uppsala University Hospital between 2016 and 2019 with laboratory-confirmed acute neuroborreliosis. Their proteomic results, based on serum and CSF analyses, were compared with the 158 patients in Cohort 1. The expression and the concentration of potential biomarkers in each patient's serum and CSF samples were measured based on two multiplex protein panels enabling simultaneous analysis of 92 inflammatory and neurology biomarkers. The PTLDS patient subgroup showed no nominally significant proteins compared to the other CVI patients in Cohort 1. However, CVI patients with signs of inflammation, which were evenly distributed in Cohort 1, showed 16 significantly (p <0.05) different proteins in both CSF and serum, but no association was seen with laboratory-confirmed exposure to Borrelia spp or other TBIs. When comparing the two cohorts, different protein profiles were observed, with 125/148 significantly different proteins in CSF and 93/174 in serum, in patients with laboratory confirmed acute neuroborreliosis, of which 6 in CSF and 6 in serum were significant at the p <0.001 level. In this first comprehensive inflammatory and neurological biomarker profile study no differences in biomarker profiles were detected between patients with PTLDS and patients with similar persisting symptoms but who did not meet the PTLDS criteria, regardless of whether laboratory verified previous exposure to Borrelia or other TBI's were present. However, the expressed markers differed from those found in patients with confirmed acute neuroborreliosis, which does not support the view that PTLDS reflects an ongoing Borrelia infection. Further studies are needed to understand and assess the usefulness of biosignatures of patients with PTLDS before they can be applied in a clinical setting.

Gene set predictor for post-treatment Lyme disease

Lyme disease (LD) is tick-borne disease whose post-treatment sequelae are not well understood. For this study, we enrolled 152 individuals with symptoms of post-treatment LD (PTLD) to profile their peripheral blood mononuclear cells (PBMCs) with RNA sequencing (RNA-seq). Combined with RNA-seq data from 72 individuals with acute LD and 44 uninfected controls, we investigated differences in differential gene expression. We observe that most individuals with PTLD have an inflammatory signature that is distinguished from the acute LD group. By distilling gene sets from this study with gene sets from other sources, we identify a subset of genes that are highly expressed in the cohorts but are not already established as biomarkers for inflammatory response or other viral or bacterial infections. We further reduce this gene set by feature importance to establish an mRNA biomarker set capable of distinguishing healthy individuals from those with acute LD or PTLD as a candidate for translation into an LD diagnostic.

A multimodal neuroimaging study of brain abnormalities and clinical correlates in post treatment Lyme disease.

Lyme disease is the most common vector-borne infectious disease in the United States. Post-treatment Lyme disease (PTLD) is a condition affecting 10–20% of patients in which symptoms persist despite antibiotic treatment. Cognitive complaints are common among those with PTLD, suggesting that brain changes are associated with the course of the illness. However, there has been a paucity of evidence to explain the cognitive difficulties expressed by patients with PTLD. This study administered a working memory task to a carefully screened group of 12 patients with well-characterized PTLD and 18 healthy controls while undergoing functional MRI (fMRI). A subset of 12 controls and all 12 PTLD participants also received diffusion tensor imaging (DTI) to measure white matter integrity. Clinical variables were also assessed and correlated with these multimodal MRI findings. On the working memory task, the patients with PTLD responded more slowly, but no less accurately, than did controls. FMRI activations were observed in expected regions by the controls, and to a lesser extent, by the PTLD participants. The PTLD group also hypoactivated several regions relevant to the task. Conversely, novel regions were activated by the PTLD group that were not observed in controls, suggesting a compensatory mechanism. Notably, three activations were located in white matter of the frontal lobe. DTI measures applied to these three regions of interest revealed that higher axial diffusivity correlated with fewer cognitive and neurological symptoms. Whole-brain DTI analyses revealed several frontal lobe regions in which higher axial diffusivity in the patients with PTLD correlated with longer duration of illness. Together, these results show that the brain is altered by PTLD, involving changes to white matter within the frontal lobe. Higher axial diffusivity may reflect white matter repair and healing over time, rather than pathology, and cognition appears to be dynamically affected throughout this repair process.

Non-specific symptoms and post-treatment Lyme disease syndrome in patients with Lyme borreliosis: a prospective cohort study in Belgium (2016–2020)

BackgroundPatients with Lyme borreliosis (LB) may report persisting non-specific symptoms such as fatigue, widespread musculoskeletal pain or cognitive difficulties. When present for more than 6 months and causing a reduction in daily activities, this is often referred to as post-treatment Lyme disease syndrome (PTLDS). This study aimed to compare the occurrence of symptoms between LB patients and controls, to estimate the proportion of LB patients developing PTLDS and to identify risk factors.MethodsA prospective cohort study was set up including three subpopulations: patients with an erythema migrans (EM) (i) or disseminated/late LB (ii) and a non-LB control group (iii). At 6- and 12-months follow-up, the occurrence of several symptoms, including six symptoms used to define PTLDS, i.e. muscle pain, joint pain, fatigue, memory problems, difficulties concentrating and problems finding words, and impact on daily activities, was compared between LB patients and controls. Finally, the proportion of LB patients developing PTLDS as defined by the Infectious Disease Society of America was estimated, including a time frame for symptoms to be present.ResultsAlthough the risk of presenting PTLDS-related symptoms was significantly higher in EM patients (n = 120) compared to controls (n = 128) at 6 months follow-up, the risk of presenting at least one of these symptoms combined with impact on daily activities was not significantly higher in EM patients, at either 6- or 12-months follow-up. A significant association was found between disseminated/late LB (n = 15) and the occurrence of any PTLDS-symptom with an impact on daily activities at both time points. The proportion of patients with PTLDS was estimated at 5.9% (95% CI 2.7–12.9) in EM patients and 20.9% (95% CI 6.8–64.4) in patients with disseminated/late LB (RR = 3.53, 95% CI 0.98–12.68, p = 0.053). No significant risk factors were identified, which may be explained by small sample sizes.ConclusionsIn our study, PTLDS was present in both LB cohorts, yet with a higher percentage in disseminated/late LB patients. Additional research is needed into risk factors for and causes of this syndrome. In addition, development and validation of standardized methods to assess the PTLDS case definition, easily applicable in practice, is of great importance.