Post-treatment Lyme Disease Research Articles

Symptoms after Lyme disease: What's past is prologue.

Protracted fatigue and other symptoms can occur after Lyme disease and other infections, with numerous possible drivers. Studies on posttreatment Lyme disease have been inconclusive, with no confirmed biomarker emerging. Prolonged antibiotic therapy provides no benefit. Thus, a holistic approach toward understanding and treating this complex disease is necessary.

A Review of Force Health Protection Aspects of Lyme Disease in the U.S. Military.

Lyme disease (LD) is an underrated threat to the military that negatively impacts mission readiness. Lyme disease has traditionally been thought to only be a risk in an operational context, where training or deployments are frequently conducted in heavily wooded environments. However, this view diminishes risks posed by many off-duty outdoor recreational activities. Furthermore, although the Army introduced a permethrin factory-treated Army Combat Uniform in 2012, permethrin retention and subsequent protection have been shown to decrease significantly after 3 months of wear. Thus, although LD is a known health risk that threatens unit readiness, beyond using treated uniforms there has been little progress at the unit level to address this threat. Focusing on a narrative review of LD and its impact on U.S. military force health protection, sources included DoD websites and policies, government press releases and information papers from sources like the CDC and FDA, and scholarly peer-reviewed journals with full-text access from the online databases EBSCOhost, MEDLINE, SCOUT, and Google Scholar. Searches included the following key words: LD and military, Army, etiology, epidemiology, incidence, treatments, post-treatment LD, and chronic LD. Articles were selected for review based on the relevance of their abstracts and titles. Although the incidence of LD appears to be increasing among service members, it is difficult to attribute this increase to military-related duties. Also, despite ongoing LD research specifically conducted and funded by the DoD, there are limited data on the mitigating effects of force education and permethrin-treated uniforms on the LD threat. Therefore, it is reasonable to conclude that LD negatively impacts military readiness and monetary costs diverted from other priorities. Lyme disease poses a genuine threat to the health and careers of service members and is an often-overlooked disruptor to military operations. Simple, feasible prevention strategies that are tailored to high-risk geographic regions can be emphasized by military units to reduce the incidence of on-duty and off-duty cases. Additionally, there remains a critical need for new preventative and diagnostic measures for LD.

Invalidation by medical professionals in post-treatment Lyme disease

Patients with post-treatment Lyme disease (PTLD) report negative perceptions of care and significant invalidation from medical professionals. However, the relationship of invalidation to illness severity has not been examined, nor have risk factors for invalidation been identified. This cross-sectional study enrolled 80 patients who met stringent criteria for PTLD. We examined correlations between the Illness Invalidation Inventory and measures of symptom severity, quality of life, and trust in physicians. To study the relationship between invalidation and potential demographic and clinical factors, we generated simple unadjusted and multivariate adjusted linear regression models. We found that higher ‘lack of understanding’ and ‘discounting’ subscale scores of the Illness Invalidation Inventory were significantly positively correlated with higher symptom severity, lower quality of life, and lower trust in physicians. In adjusted linear regression models, older age (lack of understanding: β = − 0.17, p = 0.008, discounting: β = − 0.19, p = 0.001, every 10 years) and male gender (lack of understanding: β = − 0.49, p = 0.016, discounting: β = − 0.51, p = 0.006) were associated with less invalidation. We also identified receiving an alternative diagnosis for PTLD as a mediator in the relationship between gender and invalidation. Based on our findings, we hypothesize that reducing invalidation within the clinical encounter could positively affect illness burden and quality of life for patients with PTLD.

Insights From Omics in Lyme Disease.

Lyme disease is a zoonotic infection due to Ixodes tick-transmitted Borrelia burgdorferi sensu lato spirochetes and the most common vector-borne disease in the Northern Hemisphere. Despite nearly 50 years of investigation, the pathogenesis of this infection and its 2 main adverse outcomes-postinfectious Lyme arthritis and posttreatment Lyme disease syndrome-are incompletely understood. Advancement in sequencing and mass spectrometry have led to the rapid expansion of high-throughput omics technologies, including transcriptomics, metabolomics, and proteomics, which are now being applied to human diseases. This review summarizes findings of omics studies conducted on blood and tissue samples of people with acute Lyme disease and its postinfectious outcomes.

Persistent Symptoms After Lyme Disease: Clinical Characteristics, Predictors, and Classification.

Persistent symptoms after an infection have been described for a number of infectious diseases, including Lyme disease. Studies have confirmed a moderate but consistent increase in the prevalence of such symptoms after Lyme disease, though the risk increase varies dependent on study design and the definition of persistent symptoms. Various possible predictors have been proposed, including a dysregulation of the immune system, metabolic changes, increased sensitization to pain signals, cognitive-behavioral factors, or-controversially-the persistence of the causative Borrelia bacteria or remnants thereof. Research on the precise roles of any of these factors is still ongoing. The lack of biological underpinning also makes it difficult to assess with certainty which patients' (generally nonspecific) persistent symptoms are etiologically related to the previous Lyme disease episode and which are not, particularly as these symptoms occur in the general population relatively frequently. The diagnostic criteria for posttreatment Lyme disease syndrome have shown their usefulness in both clinical and research settings but leave out a number of patients whose symptoms may fall just outside said criteria. Though the relationship between these symptoms and the previous Lyme disease episode may be very uncertain, we would argue that a uniform description and classification of these patients will aid in future research and patient management, regardless of the eventual underlying cause. Thus, we argue for an inclusive classification system for all persistent symptoms attributed to Lyme disease in order to promote validation of patient experiences and perspectives, while also maintaining scientific nuance regarding the very uncertain etiology of these patients' symptoms.

Biomarker-Based Analysis of Pain in Patients with Tick-Borne Infections before and after Antibiotic Treatment.

Tick-borne illnesses (TBIs), especially those caused by Borrelia, are increasingly prevalent worldwide. These diseases progress through stages of initial localization, early spread, and late dissemination. The final stage often leads to post-treatment Lyme disease syndrome (PTLDS) or chronic Lyme disease (CLD), characterized by persistent and non-specific multisystem symptoms affecting multiple systems, lasting over six months after antibiotic therapy. PTLDS significantly reduces functional ability, with 82-96% of patients experiencing pain, including arthritis, arthralgia, and myalgia. Inflammatory markers like CRP and TNF-alpha indicate ongoing inflammation, but the link between chronic pain and other biomarkers is underexplored. This study examined the relationship between pain and biomarkers in TBI patients from an Irish hospital and their response to antibiotic treatment. Pain ratings significantly decreased after antibiotic treatment, with median pain scores dropping from 7 to 5 (U = 27215.50, p < 0.001). This suggests a persistent infection responsive to antibiotics. Age and gender did not influence pain ratings before and after treatment. The study found correlations between pain ratings and biomarkers such as transferrin, CD4%, platelets, and neutrophils. However, variations in these biomarkers did not significantly predict pain changes when considering biomarkers outside the study. These findings imply that included biomarkers do not directly predict pain changes, possibly indicating allostatic load in symptom variability among long-term TBI patients. The study emphasizes the need for appropriate antibiotic treatment for TBIs, highlighting human rights issues related to withholding pain relief.

Retrograde and semantic amnesia in a case of post-treatment Lyme disease syndrome: did something lead to a psychogenic memory loss? A single-case study

ABSTRACT Objective: To describe a case of Post-Treatment Lyme Disease Syndrome (PTLDS) with an atypical cognitive profile. Method: A 41-year-old PTLDS patient underwent comprehensive neuropsychological testing and psychological assessment. Results: The patient exhibited impaired intensive attention but preserved selective attention. Executive functions were normal. Short-term and anterograde memory were intact, while retrograde and semantic memory were significantly impaired. The patient also experienced identity loss, specific phobias, dissociative symptoms, and depressed mood. Conclusions: Severe episodic-autobiographical and retrograde semantic amnesia was consistent with some reports of dissociative amnesia. Loss of identity and phobias were also highly suggestive of a psychogenic mechanism underlying amnesia.

What Makes It Tick: Exploring the Mechanisms of Post-treatment Lyme Disease Syndrome.

Post-treatment Lyme disease syndrome (PTLDS), which may also be referred to incorrectly as "chronic Lyme disease," is defined by the Infectious Diseases Society of America (IDSA) as the presence of fatigue, pain, and/or cognitive complaints with the functional impact that persists for more than six months after completing treatment for Lyme disease (LD). These symptoms occur in 10%-20% of patients previously diagnosed with LD caused by the bacteria Borrelia burgdorferi and appropriately treated with a course of antibiotics. The symptoms of PTLDS can be easily overlooked or misdiagnosed as a psychiatric manifestation in geographic locations that rarely see LD. In contrast, geographic locations with a higher prevalence of LD may be more aware of PTLDS symptoms and have higher clinical suspicion leading to this diagnosis. The pathophysiology behind the persistent symptoms some people experience from a primary infection is still largely unknown. Some mechanisms that have been proposed include permanent tissue damage and inflammation, immune system dysfunction, autoimmune response, co-infection, and even persistent infection refractory to treatment. We propose that ongoing PTLDS symptoms seem to be related to an autoimmune response to the tissue damage and inflammation caused by the viable or nonviable spirochete pathogen. At this point, PTLDS is diagnosed clinically as no quantifiable methods are available from laboratory or tissue diagnostics as of 2024. Similar pathophysiological features of PTLDS are seen in diseases such as COVID-19 or chronic fatigue syndrome (CFS). More effective diagnostic approaches might include further studies looking at a possible connection in the genomes of individuals developing PTLDS, quantifiable biomarkers, common inflammatory markers/pathways, and careful histopathological studies of human tissues.

A distinct autoimmune signature in Post-treatment Lyme Disease Syndrome (PTLD)

Abstract Post-Treatment Lyme Disease (PTLD) is characterized as a persistent inflammatory condition in a large fraction of patients following antibiotic treatment for Borreliella infection, but what leads to PTLD is not known. Here, we analyzed 56 peripheral blood mononuclear cell (PBMC) samples from 23 individuals at risk for PTLD in a multi-year longitudinal study via single-cell RNA sequencing. We found a significant association between an expanded subset of pro-inflammatory monocytes and Lyme disease, a phenomenon notably more prevalent in PTLD patients compared to individuals who have returned to health (RTH). Furthermore, PTLD patients exhibited a range of autoimmune-related phenotypes, absent in healthy and RTH individuals, including a positive correlation between disease severity and CD8+ KIR+ Tregs, functional impairment of CD4+ FOXP3+ Tregs, and heightened lymphocyte cytotoxicity. Interestingly, these phenotypes are associated with the stimulation by a specific peptidoglycan produced by Borreliella and this may be a key driver of PTLD. These findings hold significant potential for the development of targeted therapeutic strategies for PTLD, potentially transforming patient prognosis.

A prospective study of patients with post treatment Lyme disease syndrome treated with modified VFEM energy.

We previously demonstrated a possible therapeutic benefit of VFEM (variable frequency electromagnetic energy) technology for the treatment of Post Treatment Lyme Disease Syndrome (PTLDS) or Chronic Lyme Disease (CLD). As a result, we prospectively enrolled 10 patients, all having significant debility, to determine to what extent we could improve their quality of life. Eight patients completed the 10 treatments. All eight patients had a significant improvement in quality of life within a 4-month time frame. VFEM is a stand-alone modality that appears to demonstrate a significant improvement in quality of life in PTLDS or CLD with little or no risk or side effects of treatment.

Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome?

Dysautonomia, or dysfunction of the autonomic nervous system (ANS), may occur following an infectious insult and can result in a variety of debilitating, widespread, and often poorly recognized symptoms. Dysautonomia is now widely accepted as a complication of COVID-19 and is an important component of Post-Acute Sequelae of COVID-19 (PASC or long COVID). PASC shares many overlapping clinical features with other infection-associated chronic illnesses including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Treatment Lyme Disease Syndrome (PTLDS), suggesting that they may share common underlying mechanisms including autonomic dysfunction. Despite the recognition of this complication of Lyme disease in the care of patients with PTLD, there has been a scarcity of research in this field and dysautonomia has not yet been established as a complication of Lyme disease in the medical literature. In this review, we discuss the evidence implicating Borrelia burgdorferi as a cause of dysautonomia and the related symptoms, propose potential pathogenic mechanisms given our knowledge of Lyme disease and mechanisms of PASC and ME/CFS, and discuss the diagnostic evaluation and treatments of dysautonomia. We also outline gaps in the literature and priorities for future research.

Mismatch between subjective and objective dysautonomia

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women’s Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective–objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Annexin A2 antibodies in post-treatment Lyme disease.

Anti-annexin A2 (AA2) antibodies have been described in Lyme arthritis and erythema migrans, although they have not been described in post-treatment Lyme disease (PTLD). Determine whether anti-AA2 antibodies are present among patients with PTLD and determine the clinical relevance of these antibodies. Anti-AA2 levels were tested serially in a longitudinal cohort of 44 patients with acute Lyme disease, 22 with a return to health (EM RTH), and 22 with PTLD. Anti-AA2 antibodies were also assessed in a cross-sectional group of 281 patients with PTLD. Anti-AA2 antibodies were highest after antimicrobial therapy in both the EM RTH and PTLD cohorts. By 6 months, there was no difference between EM RTH and healthy controls. Anti-AA2 antibodies were higher in the cross-sectional PTLD group (79.69 versus 48.22 units, p < 0.0001), though with no difference in total symptom burden. Anti-AA2 persists in PTLD, though did not identify a clinical phenotype.

What patients tell us: Assessing feedback and perspectives of patients with post-treatment Lyme disease symptoms.

While most patients with Lyme disease fully recover within 6 months, a minority of patients develop significant and persistent symptoms after appropriate antibiotic treatment. With no clear pathophysiology or treatment, post-treatment Lyme disease (PTLDS) (also sometimes referred to as chronic Lyme) is a highly contested condition within the medical community. After conducting a phone survey of 25 patients who had visited an outpatient, academic center for Lyme and other tick-borne diseases, we collected and summarized patients’ perspectives and feedback of the care they received for ongoing Lyme-related symptoms. Findings from this phone survey demonstrated an extremely varied history with regards to experiences with diagnosis, treatment, and management of long-term symptoms. Key themes include a wide-ranging but life-altering self-reported symptomatology, pervasive doubts/frustrations in the medical system regarding treatment of PTLDS symptoms, and how often patients tried unconventional and nontraditional treatment methods. Importantly, patients were unified in their appreciation for an approachable and validating healthcare team even if they did not find complete resolution in their symptoms.

Advancements In Diagnostics, Treatments and Precision Medicines of Lyme Diseases – A Review

The incidence of Lyme disease, which is caused by the bacteria Borrelia burgdorferi and is transmitted by ticks in 77% of cases, has significantly increased. Skin rashes, neurological, dermatological, cardiovascular, and musculoskeletal problems are all brought on by the illness. Ten to twenty percent of individuals with post-treatment Lyme disease syndrome (PTLDS) do not improve after receiving treatment. It is essential to comprehend the traits of Borrelia burgdorferi in order to create Lyme disease diagnostic equipment and treatments. Since North America has the highest prevalence of infected black-legged ticks, the disease is spread by their bite. Preventing health issues requires early detection and treatment. Lyme disease is diagnosed using diagnostic methods such as PCR, qPCR, RT-PCR, NAATs, NGS, and multiplex PCR panels. Lyme arthritis treatment, longer courses of oral antibiotics, intravenous antibiotics, and post-treatment Lyme disease syndrome are among the treatments available. Precision medicine, also known as customized medicine, tries to modify medical judgments and treatments for specific patients in light of their distinctive genetic makeup, way of life, and environment. The future treatment of Lyme disease will comprise better diagnostic equipment, sophisticated imaging methods, precision medicine, individualized vaccination plans, and patient-centered research.

886. Impact of Race on the Early Diagnosis and Treatment of Lyme Disease

Abstract Background Previous studies using single-state and Medicare surveillance data found that Black patients with Lyme Disease (LD) are more likely to present outside of the typical summer months and have higher rates of disseminated disease at diagnosis. We further explored differences in clinical presentation and early treatment of Lyme Disease by self-reported race among a large cohort of patients at an academic research clinic. Methods We abstracted data from all patients with untreated or post-treatment LD seen at the Johns Hopkins Lyme Disease Research Center (LDRC)—either for clinical care or research participation. Patients self-reported their demographics, and clinical information regarding their initial Lyme presentation was either recorded at the time of diagnosis or was abstracted from prior, external medical records. We examined the distribution of race across initial LD clinical presentations—categorized as 1) erythema migrans (EM) rash only, 2) disseminated disease, or 3) non-specific symptoms only—using chi-squared or Fisher’s exact test and fit logistic regression models. We compared racial differences in time to appropriate treatment using a one-sided Mann-Whitney test. Results Of 1363 individuals seen at the LDRC, 93% were white, 3% were Black, 2% were Asian, and 3% self-identified as either ‘other’ or more than one race. Compared to white patients, Black patients were less likely to present with erythema migrans (EM) rash (p &amp;lt; 0.0001) and more likely to present with disseminated disease or non-specific symptoms (p=0.009, p=0.019, respectively). Black patients were more likely to have received a course of inappropriate antibiotic therapy ( 16.7% vs 8.0 %, p= 0.058). Also, Black patients with EM rash experienced longer time to appropriate treatment (16.3 days vs 4.0, p=0.062). Number of asterisks indicates degree of statistical significance. N/S means "non-significant" Conclusion We identified several racial disparities in the early detection and treatment of Lyme Disease, highlighting the need for increased awareness of Lyme and its early manifestations among patients of color and the front-line clinicians who care for them. Because darker skin tones are generally under-represented in medical textbooks and patient education materials, we include several examples of EM rashes from Black patients seen at the LDRC (Figure 2). Disclosures John Aucott, MD, Pfizer, Inc.: Advisor/Consultant

Diagnosis and treatment of “chronic Lyme”: primum non nocere

BackgroundApproximately 10% of patients experience prolonged symptoms after Lyme disease. PTLDS (post treatment Lyme disease syndrome) is a controversial topic. It has been described as a source of overdiagnosis and off-label treatment. This review aims to describe the diagnostic errors and adverse events associated with the diagnosis and treatment of PTLDS.Methodssystematic review of the literature in the Medline and Cochrane Library databases, according to PRISMA criteria, including randomized clinical trials (RCT), observational studies, and case reports addressing diagnostic errors and adverse events published between January 2010 and November 2020 in English or French. Selection used a quadruple reading process on the basis of the titles and abstracts of the different articles, followed by a full reading.Results17 studies were included: 1 RCT, 6 observational studies and 10 case reports. In the 6 observational studies, overdiagnosis rates were very high, ranging from 80 to 100%. The new diagnoses were often psychiatric, rheumatological and neurological. Disorders with somatic symptoms were often cited. Diagnostic delays were identified for cancers and frontoparietal dementia. In the RCT and observational studies, prolonged anti-infective treatments were also responsible for adverse events, with emergency room visits and/or hospitalization. The most common adverse events were diarrhea, sometimes with Clostridium difficile colitis, electrolyte abnormalities, sepsis, bacterial and fungal infections, and anaphylactic reactions.ConclusionThis review highlights the risks of prolonged anti-infective treatments that have not been proven to be beneficial in PTLDS. It emphasizes the ethical imperative of the “primum non nocere” principle, which underscores the importance of not causing harm to patients. Physicians should exercise caution in diagnosing PTLDS and consider the potential risks associated with off-label treatments.

Diagnosis, Treatment and Prevention of Pediatric Lyme disease

Lyme disease remains a significant public health challenge in the United States, particularly in the Northeast and Midwest regions, and is likely to increase in the coming years with population growth to suburban areas and warmer weather. Lyme disease is a bacterial infection caused by the spirochete, Borrelia burgdorferi, that is transmitted to humans through deer ticks. The presentation of Lyme disease can involve multiple systems with dermatologic, neurologic, rheumatologic, and cardiac symptoms commonly described. However, there is substantial variation in the presentation of Lyme disease, creating a challenge to diagnosis and treatment. The standard treatment for Lyme disease is administration of antibacterial agents. Although the majority of pediatric patients achieve symptom resolution with treatment, a subset continues to experience fatigue, pain, and psychological disturbances known as post-treatment Lyme disease syndrome. Prevention of Lyme disease largely relies on behavioral measures such as wearing long sleeves and pants and checking for ticks given the absence of an effective vaccine. Prophylactic antibiotic treatment is also highly effective for children who have experienced a Ixodes tick bite, occurring in an endemic region with tick attachment for at least 36 hours. Although Lyme disease disproportionately impacts children, the existing literature primarily focuses on its presentation in adults. In this review, we summarize the latest literature surrounding the diagnosis, treatment, and prevention of Lyme disease with a specific emphasis on pediatric populations and the recent advancements in vaccine development.

Developing a Blood Cell-Based Diagnostic Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Peripheral Blood Mononuclear Cells.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by debilitating fatigue that profoundly impacts patients' lives. Diagnosis of ME/CFS remains challenging, with most patients relying on self-report, questionnaires, and subjective measures to receive a diagnosis, and many never receiving a clear diagnosis at all. In this study, a single-cell Raman platform and artificial intelligence are utilized to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. These results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%). Additionally, specific Raman peaks that correlate with ME/CFS phenotypes and have the potential to provide insights into biological changes and support the development of new therapeutics are identified. This study presents a promising approach for aiding in the diagnosis and management of ME/CFS and can be extended to other unexplained chronic diseases such as long COVID and post-treatment Lyme disease syndrome, which share many of the same symptoms as ME/CFS.

Neuropsychiatric Lyme Disease and Vagus Nerve Stimulation.

Lyme disease, the most common tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi. While most patients with acute Lyme disease recover completely if treated with antibiotics shortly after the onset of infection, approximately 10-30% experience post-treatment symptoms and 5-10% have residual symptoms with functional impairment (post-treatment Lyme disease syndrome or PTLDS). These patients typically experience pain, cognitive problems, and/or fatigue. This narrative review provides a broad overview of Lyme disease, focusing on neuropsychiatric manifestations and persistent symptoms. While the etiology of persistent symptoms remains incompletely understood, potential explanations include persistent infection, altered neural activation, and immune dysregulation. Widely recognized is that new treatment options are needed for people who have symptoms that persist despite prior antibiotic therapy. After a brief discussion of treatment approaches, the article focuses on vagus nerve stimulation (VNS), a neuromodulation approach that is FDA-approved for depression, epilepsy, and headache syndromes and has been reported to be helpful for other diseases characterized by inflammation and neural dysregulation. Transcutaneous VNS stimulates the external branch of the vagus nerve, is minimally invasive, and is well-tolerated in other conditions with few side effects. If well-controlled double-blinded studies demonstrate that transcutaneous auricular VNS helps patients with chronic syndromes such as persistent symptoms after Lyme disease, taVNS will be a welcome addition to the treatment options for these patients.