Borrelia Infection (Lyme Disease)

Background Imaging of neuroinfections is well documented, however with several restrictions due to the heterogeneity of pathogens. Lyme neuroborreliosis (LNB) is a tick-borne infection, caused by Borrelia burgdorferi sensu lato complex (Bb) and among the most prevalent bacterial infections of the nervous system. Due to climatic and environmental changes, the incidence of tickborne diseases is increasing throughout Europe, in Denmark the annual incidence is estimated to 3-4/100,000. Adults mainly manifests as a self-limiting subacute painful meningoradiculitis, lymphocytic meningitis and/or cranial nerve palsy, symptoms of CNS involvement such as acute encephalitis and myelitis are rare. Over time, most cases of Bb infection is thought to be self-resolving, however antibiotics accelerate the process by eradicating the pathogen and reduces the risk of disseminated late infection and persistent symptoms. The response to antibiotics can be slow, but the majority of patients report marked improvement in symptoms after treatment, a proportion of patients, do however report to experience persistent residual symptoms including fatigue, pain or cognitive disturbances and studies have suggested that late diagnosis and the burden of symptoms at time of treatment initiation increases the risk of these symptoms. If antibiotic treatment is initiated as early as possible, LNB has a very good prognosis, early diagnosis and treatment initiation are therefore of paramount interest. As no markers in plasma can be used to diagnose or follow LNB, the diagnosis of LNB is based on clinical symptoms in combination with elevated white blood cell count in cerebrospinal fluid (CSF) and the detection of specific Bb intrathecal antibody production. However, Bb serology has several disadvantages in the ability to confirm active disease and monitor disease activity and response to antibiotic treatment. Bb antibodies in CSF are first detectable weeks after onset of the neuroinfection and they may persist for years even after the disease has been well-treated. In addition, symptoms can be unspecific, evolving over time and even mimic other neurological diseases potentially resulting in misdiagnosis, diagnostic delay and reduced patient outcome. The investigators recently reported a median duration of neurological symptoms before first hospital contact of 21 days in a Danish nationwide prospective cohort study of 194 LNB patients included between 2015-2018. Currently, the only way to monitor disease activity - although not ideal - is to to perform a re-lumbar puncture, which is an invasive procedure, not always possible or successful and with risk of post lumbar puncture headache which develops in 10-20% of the patients. Improving diagnosis, ideally non-invasively, is therefore of great interest and new methods to confirm active disease and monitor the effect of treatment an important field of research which might promote a shift from empirical treatment to personalized medicine with expected improvement in patient outcome. Non-invasive imaging seems an obvious solution. The investigators have retrospectively studied the value of CT and MRI in diagnosis of LNB and found no value of computerized tomography (CT)-head and limited value of magnetic resonance imaging (MRI)-Brain/Spine. Regarding use of positron emission tomography (PET) the most commonly used ligand for infection and inflammation imaging is the radiolabeled glucose analogue, fluorine-18-fluorodeoxyglucose (18F-FDG). However, 18F-FDG has major limitations including low specificity, as it is taken up by any cell with increased glucose metabolism including but not restricted to leukocytes, macrophages, monocytes, lymphocytes and giant cells. In addition, as the normal brain has high glucose consumption, it is difficult (impossible) to obtain sufficient contrast in LNB as inflammation is primarily in the meninges. Indeed, the investigators have confirmed from cases of LNB that had 18F-FDG-PET could not be used. Due to these limitations, there is an unmet need for other, more specific, targeted radioligands to improve imaging of infectious diseases e.g. LNB and the adjacent inflammatory response. Macrophages is a potential and promising target for the diagnosing of more specific infections and in particular LNB. Macrophages have anti-inflammatory properties with high phagocytic activity, and they are not only involved in the early immune response but present as long as the infection is active. Macrophage activation can be monitored by the circulating biomarker soluble CD163, the intrathecal inflammation in LNB does not lead to any or only very subtle peripheral measurable changes of normal infectious parameters even with highly active but localized infection as in LNB. As activated macrophages overexpresses somatostatin receptor subtype 2 (sstr2), the activity of macrophages can be visualized by PET imaging targeting sstr2 using the ligand 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid\]-d-Phe1,Tyr3-octreotate (DOTATATE). At Rigshospitalet the investigators recently developed 64Cu-DOTATATE with a physical half-life of 12.7 hours (vs. 1 hour) and a 4-fold better theoretical (positron range) spatial resolution compared to existing 68Ga-labeled tracers. These characteristics are a prerequisite. Accordingly, the investigators found in a pre-clinical trial that 64Cu-DOTATATE was able to non-invasively detect and monitor Lyme borreliosis in a murine model of Lyme arthritis and that delayed imaging, later than 3 h and ideally 24 h post injection, was necessary to obtain good target-to-background ratios in images of Bb infection. In humans, the investigators previously demonstrated that 64Cu-DOTATATE-PET could visualize macrophages in vivo in atherosclerotic, carotid plaques prior to endarterectomy. Gene expression analysis on the excised plagues demonstrated at close correlation between CD163 gene expression and PET tracer uptake confirming that it was indeed macrophages that were visualized. In this prospective, observational cohort study with 64Cu-DOTATATE, the investigators wish to include a total of 50 patients clinically suspected of LNB. The investigators will investigate the diagnostic value of 64Cu-DOTATATE-PET comparing clinically suspected and CSF verified LNB patients with clinically suspected patients without CSF verification. The investigators further wish to explore if the biomarkers sCD163, NfL, and Tau may contribute to the diagnostics of LNB, and if 64Cu-DOTATATE PE/CT/MRI have a prognostic value by including a follow-up visit 6 months after treatment, comparing patients with persistent symptoms to patients without persistent symptoms. The investigators hypothesize that the information obtained from 64Cu-DOTATATE PET/CT/MRI and the biomarkers sCD163 and NfL can improve the diagnostics of LNB. The investigators also hypothesize that 64Cu-DOTATATE PET/CT/MRI will be able to contribute to the follow-up of patients by adding prognostic information and the risk of persistent symptoms. The application of 64Cu-DOTATATE PET/CT/MRI in the diagnostic work-up of LNB would thus expectedly lead to a more precise diagnosis and risk assessment.

Lyme disease has emerged as the leading vector-borne disease in the United States. Despite how much has been learned about Lyme borreliosis in the past decade, there are still many remaining areas of uncertainty. One fundamental question is whether persistent signs and symptoms of disease, despite the administration of what is currently considered to be adequate antibiotic therapy, are due to ongoing active borrelial infection, to a post-infectious syndrome, to irreversible sequelae of earlier tissue injury or due to a condition unrelated to Lyme disease. Reliable objective markers of infection, of clinical status and of host responses to the organism are required to discern the scope and the implications of persistent borrelial infection, the effectiveness of current treatment options, and the development of new therapeutic approaches. The goal of this study is to assemble and follow a well-characterized cohort of patients with post-treatment Lyme disease syndrome and relevant controls that will yield a prospective database upon which stringent diagnostic criteria can be established and future therapeutic trials can be designed.

Clinical, biological, radiological, and pharmacological description of cases of disseminated borreliosis (Borrelia burgdorferi sl. and Borrelia miyamotoi) occurring in patients who received drug treatment based on anti-CD20 monoclonal antibodies.

This Phase 1 study is designed to assess the safety, tolerability, and pharmacokinetics of single and multiple intravenous doses of BWC0977 when administered to healthy adult volunteers. This is a randomized double-blind, placebo-controlled, ascending dose, multi-cohort trial. A total of 64 healthy volunteers are expected to be enrolled in 8 Cohorts. The study will be conducted in two phases: A single ascending dose (SAD) phase, followed by a multiple ascending dose (MAD) phase. In SAD, participants in Cohorts 1 - 2 will receive one dose of BWC0977 or placebo. In MAD, participants in cohorts 3 - 7 will receive multiple doses of BWC0977 or placebo for 7-10 consecutive days (as per the schedule). In both parts, sequential cohorts will be exposed to increasing doses of BWC0977.

Background: Lyme disease (LD) is the most common tick born disease in Europe. It is caused by an infection with several genospecies of the spirochaetal bacteria Borrelia burgdorferi (Bb). Although classical disease manifestations are well-known, the clinical presentation in children is often variable and inconclusive, which results in delayed diagnosis and treatment. Methods/design: The investigators are conducting an observational cohort study in children with LD. Study site is the University Children's Hospital Zurich. 502 patients will be enrolled. Children from 0-17 years of age presenting with signs and symptoms suspicious for LD are included in the study. Previously healthy children with routine blood investigation are enrolled as healthy controls. Patients will be excluded in cases of primary or secondary immunodeficiency. Clinical and routine laboratory data regarding course and outcome, as well as venous blood samples are collected at first hospital contact and follow up visits (FUP). FUPs are scheduled at 28 days, 3 months and 6 months after hospital admission. Cerebrospinal fluid (CSF) and synovial fluid (SF) will be collected for the study only if sampling is indicated due to diagnostic or therapeutic reasons. Primary objectives are to assess Bb-specific ASCs in blood using ELISpot assay, in order to develop new diagnostic tool for early LD. In addition, the investigators will examine immune response in patients with various LD manifestations using flow cytometry, ELISA assay, and ELISpot assay. Finally, the investigators will perform whole genome sequencing of causative Bb-species isolated from patients to investigate potential differences in virulence and associations with clinical presentations. Discussion: This single-centre, observational cohort study will improve the understanding of immunological response in LD in children. It will also provide new information about the virulence of distinct LD causing Bb-genospecies and will test a new approach in the diagnosis of early LD.

Lyme disease is a public health crisis in the US. It is estimated that over 400,000 cases occur every year with 10-20% of those infected going on to develop Post-Treatment Lyme disease Syndrome (PTLDS). The goal of this study is to investigate if giving Ceftriaxone every 5 days for about 6 weeks kills the organism that produces persistent Lyme infection. Enrolled participants will be randomized 1:1 receiving either pulse-dosed ceftriaxone or placebo \[dextrose (5% in water), (D5W)\], intravenously. Participants will be evaluated at each of the study visits, and then in a follow-up phase out to 12 months. They will be unblinded at 6 months and those randomized to the placebo group will be offered pulse-dosed ceftriaxone on the same schedule as those randomized to the drug group. All patients will be followed up for a total of 12 months post treatment initiation.

This study will explore treating participants who are 18 to 75 years old with Post-Treatment Lyme Disease. IV Ceftriaxone will be delivered in a pulse dose fashion, approximately every 5 days for a total of 9 IV infusions over 6 weeks. Participants will return one month following last treatment, at approximately 3 and 6 months from study start. At each study visit, participants will be asked a number of questionnaires including the SAFTEE assessment to assess the side effects of the drug as compared to placebo; the Fatigue Severity Scale, SF-36, GSQ-30, and PROMIS-29 questionnaires to assess physical functioning, general health, vitality, social functioning, bodily pain, role physical, role emotional, mental health, symptoms, fatigue, anxiety, depression, and sleep disturbances; the CSSRS to assess suicidal ideation. At the 6-month mark, the study will be unblinded and participants in the placebo group will be invited to repeat the study visits receiving Ceftriaxone. Participants who originally received Ceftriaxone will receive a phone call follow up at 1 year. The duration for both groups is one year. Samples will be collected for safety labs and research assessments.

The investigators include data on diagnosis at admission, symptoms and signs on admission, character and timing of diagnostic work-up and treatment and outcome assessed by the Glasgow Outcome Score (GOS). Diagnostic work-up and treatment is left at the discretion of the local physician and therefore not standardised In general any symptoms/deficits should only be listed if they are 'new' to the patient, e.g. a known palsy of the facial nerve should not be listed as a new relevant finding at admission. On the other hand, worsening of a known neurological deficit should be listed under signs in the given instrument (bacterial meningitis, encephalitis, neuroborreliosis etc). Likewise, for outcome only changes in pre-morbid conditions should be listed including place of residence, functional status, neurological deficits etc. Time of admission is obtained in prioritized order from the ambulance charts or notifications of arrival by secretaries or nurses in the emergency departments. Timing of lumbar puncture and cranial imaging is extracted from the electronic records at the departments of biochemistry or radiology while timing of antibiotic therapy for meningitis is identified in electronic medication systems. Time to lumbar puncture, cranial imaging and antibiotic therapy is calculated as time from arrival at hospital to each of the above events. Quality control of case enrollment is ensured by ad hoc case-to-case discussions and at study group meetings 2-3 times a year To ensure completeness of reported CNS infections annual searches of selected International Classification of Diseases version 10 (ICD-10) codes are performed in local administrative databases at each department: A17 A32.1 A32.7 A39.0 A52.1-52.3 A69.2 (neuroborreliosis) A83 A84 A85 A87 A89 B00.3-00.4 B01.0-01.1 B02.0-02.0 B582 B451 B375 G00 G01 G02 G03 G04 G05 G06 G07

The purpose of this study is to compare the efficacy of different amoxicilline treatment regimens in patients with erythema migrans.

The purpose of this study is to compare the efficacy of 7-day versus 14-day doxycycline treatment in patients with multiple erythema migrans.