Tag: Lyme disease

A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis – chronic fatigue syndrome

Abstract:

Background: Up to 20% of Lyme disease cases experience post-treatment Lyme disease syndrome (PTLDS). The biological basis for PTLDS is poorly understood and no evidence-based treatment has been identified. Genetic studies have the potential to elucidate PTLDS pathophysiology and identify treatment targets.

Methods: We used electronic health record data (EHR) and genetic data from a linked biorepository to conduct a genome-wide association study (GWAS) for PTLDS among patients from a Pennsylvania health system. We evaluated the validity of the GWAS results in two separate conditions that have hypothesized overlapping pathophysiology, fibromyalgia and myalgic encephalomyelitis – chronic fatigue syndrome (ME/CFS). GWAS analyses were performed using logistic regression in SUGEN, assuming an additive genetic model, and adjusting for age, sex, array, and the first 10 principal components calculated from whole genome genotyping to adjust for ancestry, and accounting for relatedness including all 1st degree relationships. The functional mapping and annotation analysis (FUMA) tool was used to explore top findings from our GWAS.

Results: Among the 161,875 eligible MyCode participants with genotyping, there were 3,585 who met the criteria for treated Lyme disease. A subset of 695 (19.4%) of these patients met the criteria for PTLDS and the remaining 2890 were classified as controls. We identified two PTLDS loci that reached the suggestive significance threshold (P < 5 × 10– 7), with lead variants rs77857587, near IRX1, and rs10833979, near GAS2. Our top index single nucleotide polymorphism (SNP), rs77857587, is in high linkage disequilibrium with a long-range protein quantitative locus SNP, rs111774530, for the MARC2 (Mitochondrial Amidoxime Reducing Component 2) protein. We identified 5,041 cases of fibromyalgia (150,599 controls) and 2,268 cases of ME/CFS (151,594 controls) among the MyCode participants. Neither of the two suggestively significant loci were associated with fibromyalgia or ME/CFS.

Conclusion: We identified two PTLDS loci that reached a suggestive significance threshold. Our top index SNP is associated with the MARC2 protein, a protein that has been linked to multiple immune checkpoints. Further study is needed in a larger population to evaluate whether there is genetic evidence of the role of immune response in the occurrence of PTLDS.

Source: Hirsch AG, Justice AE, Poissant A, Nordberg CM, Josyula NS, Aucott J, Rebman AW, Schwartz BS. A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis – chronic fatigue syndrome. BMC Infect Dis. 2025 Feb 24;25(1):265. doi: 10.1186/s12879-024-10238-x. PMID: 39994562; PMCID: PMC11853495. https://pmc.ncbi.nlm.nih.gov/articles/PMC11853495/ (Full text)

Fibroblast growth factor receptor inhibitors mitigate the neuropathogenicity of Borrelia burgdorferi or its remnants ex vivo

Abstract:

In previous studies, we showed that fibroblast growth factor receptors (FGFRs) contribute to inflammatory mediator output from primary rhesus microglia in response to live Borrelia burgdorferi. We also demonstrated that non-viable B. burgdorferi can be as pathogenic as live bacteria, if not more so, in both CNS and PNS tissues.

In this study we assessed the effect of live and non-viable B. burgdorferi in inducing FGFR expression from rhesus frontal cortex (FC) and dorsal root ganglion (DRG) tissue explants as well as their neuronal/astrocyte localization. Specific FGFR inhibitors were also tested for their ability to attenuate inflammatory output and apoptosis in response to either live or non-viable organisms.

Results show that in the FC, FGFR2 was the most abundantly expressed receptor followed by FGFR3 and FGFR1. Non-viable B. burgdorferi significantly upregulated FGFR3 more often than live bacteria, while the latter had a similar effect on FGFR1, although both treatments did affect the expressions of both receptors. FGFR2 was the least modulated in the FC tissues by the two treatments. FGFR1 expression was more prevalent in astrocytes while FGFR2 and FGFR3 showed higher expression in neurons.

In the DRG, all three receptor expressions were also seen, but could not be distinguished from medium controls by immunofluorescence. Inhibition of FGFR1 by PD166866 downregulated both inflammation and apoptosis in both FC and DRG in response to either treatment in all the tissues tested.

Inhibition of FGFR1-3 by AZD4547 similarly downregulated both inflammation and apoptosis in both FC and DRG in response to live bacteria, while with sonicated remnants, this effect was seen in one of the two FC tissues and 2 of 3 DRG tissues tested. CCL2 and IL-6 were the most downregulated mediators in the FC, while in the DRG it was CXCL8 and IL-6 in response to FGFR inhibition. Downregulation of at least two of these three mediators was observed to downregulate apoptosis levels in general.

We show here that FGFR inhibition can be an effective anti-inflammatory treatment in antibiotic refractive neurological Lyme. Alternatively, two biologics may be needed to effectively curb neuroinflammation and pathology in the CNS and PNS.

Source: Parthasarathy G. Fibroblast growth factor receptor inhibitors mitigate the neuropathogenicity of Borrelia burgdorferi or its remnants ex vivo. Front Immunol. 2024 Apr 4;15:1327416. doi: 10.3389/fimmu.2024.1327416. PMID: 38638441; PMCID: PMC11024320. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024320/ (Full study)

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

Abstract:

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.

Source: Adler BL, Chung T, Rowe PC, Aucott J. Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome? Front Neurol. 2024 Feb 8;15:1344862. doi: 10.3389/fneur.2024.1344862. PMID: 38390594; PMCID: PMC10883079. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883079/ (Full text)

Long COVID Diagnostic with Differentiation from Chronic Lyme Disease using Machine Learning and Cytokine Hubs

Abstract:

The absence of a diagnostic for long COVID (LC) or post-acute sequelae of COVID-19 (PASC) has profound implications for research and potential therapeutics. Further, symptom-based identification of patients with long-term COVID-19 lacks the specificity to serve as a diagnostic because of the overlap of symptoms with other chronic inflammatory conditions like chronic Lymedisease (CLD), myalgic encephalomyelitis-chronic fatigue syndrome (ME-CFS), and others. Here, we report a machine-learning approach to long COVID diagnosis using cytokine hubs that are also capable of differentiating long COVID from chronic Lyme.

We constructed three tree-based classifiers: decision tree, random forest, and gradient-boosting machine (GBM) and compared their diagnostic capabilities. A 223 patient dataset was partitioned into training (178 patients) and evaluation (45 patients) sets. The GBM model was selected based on performance (89% Sensitivity and 96% Specificity for LC) with no evidence of overfitting.

We tested the GBM on a random dataset of 124 individuals (106 PASC and 18 Lyme), resulting in high sensitivity (97%) and specificity 90% for LC). A Lyme Index composed of two features ((TNF-alpha +IL-4)/(IFN-gamma + IL-2) and (TNF-alpha *IL-4)/(IFN-gamma + IL-2 + CCL3) was constructed as a confirmatory algorithm to discriminate between LC and CLD.

Source: Bruce Patterson, Jose Guevara-Coto, Javier Mora et al. Long COVID Diagnostic with Differentiation from Chronic Lyme Disease using Machine Learning and Cytokine Hubs, 18 January 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3873244/v1] https://www.researchsquare.com/article/rs-3873244/v1 (Full text)

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

Abstract:

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 as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Key points

  • This systematic review uses qualitative analysis to compare posttreatment Lyme disease syndrome to myalgic encephalitis/chronic fatigue syndrome, both of which are post-active phases of infection syndromes.
  • The result of this review suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Source: Bai, NA, Richardson, CS. Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and comparison of pathogenesis. Chronic Dis Transl Med. 2023; 1– 8. doi:10.1002/cdt3.74 https://onlinelibrary.wiley.com/doi/full/10.1002/cdt3.74 (Full text)

Corona With Lyme: A Long COVID Case Study

Abstract:

The longevity of the coronavirus disease 2019 (COVID-19) pandemic has necessitated continued discussion about the long-term impacts of SARS-CoV-2 infection. Many who develop an acute COVID-19 infection will later face a constellation of enduring symptoms of varying severity, otherwise known as long COVID. As the pandemic reaches its inevitable endemicity, the long COVID patient population will undoubtedly grow and require improved recognition and management. The case presented describes the three-year arc of a previously healthy 26-year-old female medical student from initial infection and induction of long COVID symptomology to near-total remission of the disease. In doing so, the course of this unique post-viral illness and the trials and errors of myriad treatment options will be chronologized, thereby contributing to the continued demand for understanding this mystifying disease.

Source: Thor DC, Suarez S. Corona With Lyme: A Long COVID Case Study. Cureus. 2023 Mar 24;15(3):e36624. doi: 10.7759/cureus.36624. PMID: 37155451; PMCID: PMC10122830. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122830/ (Full text)

Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study

Abstract:

Background: Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned.

Methods and findings: A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible.

Conclusions: UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.

Source: Brellier F, Pujades-Rodriguez M, Powell E, Mudie K, Mattos Lacerda E, Nacul L, Wing K. Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study. PLoS One. 2022 Mar 23;17(3):e0265765. doi: 10.1371/journal.pone.0265765. PMID: 35320297; PMCID: PMC8942220. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265765 (Full text)

Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease

Abstract:

Background: Prior studies have demonstrated that Lyme disease is frequently over-diagnosed. However, few studies describe which conditions are misdiagnosed as Lyme disease.

Methods: This retrospective observational cohort study evaluated patients referred for Lyme disease to a Mid-Atlantic academic center between 2000-2013 who lacked evidence for Borrelia burgdorferi infection. The primary outcome is clinically described diagnoses contributing to symptoms. Secondary outcomes included symptom duration and determination whether diagnoses were new or attributed to existing medical conditions.

Results: Of 1261 referred patients, 1061 (84%) had no findings of active Lyme disease, with 690 (65%) receiving other diagnoses resulting in 405 (59%) having newly diagnosed medical conditions, 134 (19%) attributed to pre-existing medical issues, and 151 (22%) had both new and pre-existing conditions. Among the 690 patients, the median symptom duration was 796 days, and a total of 139 discrete diagnoses were made. Infectious disease diagnoses comprised only 3.2%. Leading diagnoses were anxiety/depression 222 (21%), fibromyalgia 120 (11%), chronic fatigue syndrome 77 (7%), migraine disorder 74 (7%), osteoarthritis 62 (6%) and sleep disorder/apnea 48 (5%). Examples of less frequent but non-syndromic diseases newly diagnosed included multiple sclerosis (11), malignancy (8), Parkinson’s disease (8), sarcoidosis (4) or amyotrophic lateral sclerosis (4).

Conclusions: Most patients with long-term symptoms have either new or pre-existing disorders accounting for their symptoms other than Lyme disease, suggesting overdiagnosis in this population. Patients referred for consideration of Lyme disease for chronic symptoms deserve careful assessment for diagnoses other than Borrelia burgdorferi infection.

Source: Kobayashi T, Higgins Y, Melia MT, Auwaerter PG. Mistaken Identity: Many Diagnoses are Frequently Misattributed to Lyme Disease. Am J Med. 2021 Nov 30:S0002-9343(21)00792-0. doi: 10.1016/j.amjmed.2021.10.040. Epub ahead of print. PMID: 34861197. https://www.sciencedirect.com/science/article/pii/S0002934321007920  (Full text)

Characterising DSCATT: A case series of Australian patients with debilitating symptom complexes attributed to ticks

Abstract:

Objectives(s): To characterise the clinical profile, aetiology and treatment responsiveness of ‘Australian Lyme’, or Debilitating Symptom Complexes Attributed to Ticks.

Methods: Single-centre retrospective case analysis of patients referred to the Infectious Diseases Unit at Austin Health – a tertiary health service in Heidelberg, Australia – between 2014 and 2020 for investigation and treatment of suspected Debilitating Symptom Complexes Attributed to Ticks. Patients were included if they had debilitating symptoms suggested by either themselves or the referring clinician as being attributed to ticks.

Results: Twenty-nine Debilitating Symptom Complexes Attributed to Ticks cases were included in the analysis. Other than Lyme disease (83%), the most common prior medical diagnoses were Epstein-Barr virus (38%), chronic fatigue syndrome (28%) and fibromyalgia (24%). Prior histories of anxiety (48%) and depression (41%) were common. The most frequently reported symptoms included fatigue (83%), headache (72%) and arthralgia (69%). National Association of Testing Authorities/Royal College of Pathologists of Australasia-accredited serology was not diagnostic of acute infective causes, including Lyme disease, in any patient. Of 25 cases with available data, 23 (92%) had previously been prescribed antimicrobials, with 53% reporting benefit from them. The most common diagnoses made by our hospital were chronic fatigue syndrome (31%), migraines (28%) and fibromyalgia (21%). Only one patient’s symptoms were not accounted for by other diagnoses.

Conclusion: This is the first case series of patients with Debilitating Symptom Complexes Attributed to Ticks. They had high rates of other medically unexplained syndromes, and no evidence of acute Lyme disease, or any common organic disease process. Debilitating Symptom Complexes Attributed to Ticks remains medically unexplained, and may therefore be due to an as yet unidentified cause, or may be considered a medically unexplained syndrome similar to conditions such as chronic fatigue syndrome.

Source: Schnall J, Oliver G, Braat S, Macdonell R, Gibney KB, Kanaan RA. Characterising DSCATT: A case series of Australian patients with debilitating symptom complexes attributed to ticks. Aust N Z J Psychiatry. 2021 Sep 1:48674211043788. doi: 10.1177/00048674211043788. Epub ahead of print. PMID: 34465249. https://pubmed.ncbi.nlm.nih.gov/34465249/