Background and purpose
Currently there is an unmet need for a highly standardized blood biomarker test to monitor treatment response in Lyme neuroborreliosis (LNB). Differentiating between active or ...past infection is challenged by the relatively high frequency of persistent symptoms after the end of antibiotic treatment (estimated 15%–20%), the variable clinical course and the long‐lasting Borrelia burgdorferi antibodies. The aim was therefore to evaluate plasma neurofilament light chain (pNfL) as a marker for disease activity in LNB.
Methods
This was a prospective cohort of definite LNB (N = 36) with blood samples and clinical evaluation including Glasgow Outcome Score at treatment initiation and 3 and 6 months’ follow‐up. Consecutive plasma was retrospectively analysed for the content of neurofilament light chain by Quanterix® kits (Simoa® NF‐light Kit).
Results
Plasma neurofilament light chain significantly decreased between treatment initiation and the 3‐month follow‐up (median 83 pg/ml vs. median 14 pg/ml (25 pairs), p < 0.0001). No significant change was observed between 3 and 6 months’ follow‐up (median 14 pg/ml vs. median 12 pg/ml (21 pairs), p = 0.33). At treatment initiation 90% had pNfL above the age‐defined reference compared to only 23% and 7% respectively at 3 and 6 months’ follow‐up. Decreases in pNfL were mirrored by increasing Glasgow Outcome Score. Reporting persistent symptoms at the 6‐month follow‐up was not associated with pNfL (relative change from reference or actual values) at baseline or at 6 months’ follow‐up.
Conclusion
Plasma neurofilament light chain decreases following antibiotic treatment in LNB and is not associated with reporting persistent symptoms. It was therefore speculated that it may prove useful as a treatment response biomarker in LNB.
PurposeThe purpose of the Danish HIV Birth Cohort (DHBC) is to investigate the significance of HIV-1 infection in pregnancy and after delivery in women living with HIV (WLWH) in Denmark and their ...children, in the era of antiretroviral therapy and other interventions for treatment and prophylaxis.ParticipantsAll WLWH giving birth to one or more children in Denmark after 31 December 1999 are included, with consecutive ongoing enrolment, if they are living with HIV and pregnant, or if they are diagnosed with HIV in relation to pregnancy, delivery or shortly after delivery.Findings to dateDHBC has been used to describe trends in the management of pregnancies in WLWH and their outcomes on a nationwide basis, mode of delivery and predictors of emergency caesarean section as well as risk factors during pregnancy in WLWH for birth-related complications compared with women from the general population (WGP). We have found that HIV-exposed, but uninfected (HEU) children born to WLWH had a lower median birth weight and gestational age and were at higher risk of intrauterine growth retardation than children born to WGP. We have investigated risk of in-hospital admission and use of antibiotics during the first 4 years of life among HEU children and showed that HEU children had an increased risk of overall hospital admission compared with a matched control group of unexposed children.Further, we compared anthropometric outcomes in children with a matched control group of children not exposed to HIV.Future plansTo continuously investigate the significance of HIV infection and antiretroviral therapy in pregnancy and after delivery in WLWH in Denmark and their HEU children and compare these findings with children born to WGP.
Lyme neuroborreliosis (LNB) is a prevalent tick-borne disease in Europe caused by Borrelia burgdorferi sensu lato complex. Slightly suppressed induced Th1- and Th17-responses are seen at diagnosis. ...The induced immune response following antibiotic therapy is unknown. We hypothesized that the immune responses normalize after completing antibiotic treatment.
An observational longitudinal cohort study investigating the induced immune response in adult patients with LNB at diagnosis, three and six months after treatment. Whole blood was added to three TruCulture® (Myriad RBM, Austin, USA) tubes each containing one stimulation. An additional TruCulture® tube was without stimulation representing the in vivo activation of blood immune cells. Nine cytokines were measured using Luminex (LX200, R&D Systems, BIO-Teche LTD). Changes in immune response were analyzed with linear mixed model including follow-up as categorical fixed effect.
A total of 21 patients with 55 samples were included. All had clinical improvement, but 5/21 patients reported residual symptoms after six months. The non-induced release of IL-17A and IL-1β increased significantly from diagnosis to six month follow-up. Six months after treatment only IFN-α and TNF-α were below the reference range.
Minor variations in the induced immune responses were seen during the study period. Th1- and Th17-responses continued to be low with low IFN-γ, IL-12p40, and IL-17A in multiple stimulations.
Overall little dynamic was observed. The changes in the cytokine responses are most likely not linked to LNB pathogenesis and our results do not support the implementation of TruCulture® in the diagnostics or follow-up of LNB.
Introduction
Borrelia burgdorferi
sensu lato complex (
B. burgdorferi
) can cause a variety of clinical manifestations including Lyme neuroborreliosis. Following the tick-borne transmission,
B. ...burgdorferi
initially evade immune responses, later symptomatic infection is associated with occurrence of specific antibody responses. We hypothesized that
B. burgdorferi
induce immune hyporesponsiveness or immune suppression and aimed to investigate patients with Lyme neuroborreliosis ability to respond to immune stimulation.
Methods
An observational cohort study investigating the stimulated immune response by standardized whole blood assay (TruCulture
®
) in adult patients with Lyme neuroborreliosis included at time of diagnosis from 01.09.2018-31.07.2020. Reference intervals were based on a 5-95% range of cytokine concentrations from healthy individuals (n = 32). Patients with Lyme neuroborreliosis and references were compared using Mann-Whitney U test. Heatmaps of cytokine responses were generated using the webtool Clustvis.
Results
In total, 22 patients with Lyme neuroborreliosis (19 definite, 3 probable) were included. In the unstimulated samples, the concentrations of cytokines in patients with Lyme neuroborreliosis were comparable with references, except interferon (IFN)-α, interleukin (IL)-17A, IL-1β and IL-8, which were all significantly below the references. Patients with Lyme neuroborreliosis had similar concentrations of most cytokines in all stimulations compared with references. IFN-α, IFN-γ, IL-12 and IL-17A were lower than references in multiple stimulations.
Conclusion
In this exploratory cohort study, we found lower or similar concentrations of circulating cytokines in blood from patients with Lyme neuroborreliosis at time of diagnosis compared with references. The stimulated cytokine release in blood from patients with Lyme neuroborreliosis was in general slightly lower than in the references. Specific patterns of low IL-12 and IFN-γ indicated low Th1-response and low concentrations of IL-17A did not support a strong Th17 response. Our results suggest that patients with Lyme neuroborreliosis elicit a slightly suppressed or impaired immune response for the investigated stimulations, however, whether the response normalizes remains unanswered.
We report two cases of tularemia with different clinical manifestations, both suspected of tick-borne transmission and with near-complete remission of all symptoms within 3 months after antimicrobial ...treatment. The first patient presented with a classical ulceroglandular manifestation; general malaise, an ulcer and lymphadenopathy, occurring two weeks after a tick bite. Diagnosis was established by polymerase chain reaction of a skin biopsy from the ulcer. The second patient presented with a rare systemic manifestation including bacteremia and myocarditis resulting in severe clinical heart failure, pulmonary edema and secondary kidney failure. Previous tick bites were elucidated after the bacteremia was discovered. The cases underscore the heterogeneity of manifestations, the diagnostic approach and the importance of thorough medical history including recent exposures especially in cases with infection of unknown origin.
•sCD163 is a macrophage-specific marker detectable in blood and cerebrospinal fluid.•Levels of sCD163 in cerebrospinal fluids were elevated in neuroborreliosis.•The optimal diagnostic cut-off of ...sCD163 in cerebrospinal fluid was 210 µg/l.•Combining ReaScan-CXCL13 with sCD163 increased the diagnostic strength.•sCD163 in plasma was not elevated in patients with neuroborreliosis.
We aimed to investigate levels of the macrophage-specific marker, sCD163, in cerebrospinal fluid and plasma in patients with Lyme neuroborreliosis. We tested the diagnostic value of CSF-sCD163 and ReaScan-CXCL13 and analyzed if plasma-sCD163 could monitor treatment response.
An observational cohort study: Cohort 1—Cerebrospinal fluid from adults with neuroborreliosis (n = 42), bacterial meningitis (n = 16), enteroviral meningitis (n = 29), and controls (n = 33); Cohort 2—Plasma from 23 adults with neuroborreliosis collected at diagnosis, three, and six months.
sCD163 was determined using an in-house sandwich ELISA. ReaScan-CXCL13 measured semiquantitative concentrations of CXCL13, cut-off ≥ 250 pg/ml diagnosed neuroborreliosis.
Receiver Operating Characteristics analyzed the diagnostic strength. A linear mixed model including follow-up as categorical fixed effect analyzed differences in plasma-sCD163.
CSF-sCD163 was higher in neuroborreliosis (643 µg/l) than in enteroviral meningitis (106 µg/l, p < 0.0001) and controls (87 µg/l, p < 0.0001), but not bacterial meningitis (669 µg/l, p = 0.9). The optimal cut-off was 210 µg/l, area under the curve (AUC) 0.85. ReaScan-CXCL13 had an AUC of 0.83. Combining ReaScan-CXCL13 with CSF-sCD163 increased AUC significantly to 0.89.
Plasma-sCD163 showed little variation and was not elevated during the 6 months of follow-up.
CSF-sCD163 is diagnostic for neuroborreliosis with an optimal cut-off of 210 µg/l. Combining ReaScan-CXCL13 with CSF-sCD163 increases AUC. Plasma-sCD163 cannot monitor treatment response.
IntroductionNeoehrlichia mikurensis is a tick-borne bacterium that primarily causes disease in immunocompromised patients. The bacterium has been detected in ticks throughout Europe, with a 0%–25% ...prevalence. N. mikurensis infection presents unspecific symptoms, which can easily be mistaken for inflammatory disease activity. We aimed to determine the prevalence of N. mikurensis in rheumatological patients receiving tumour necrosis factor inhibitors (TNFi) and a cohort of healthy individuals.Materials and methodsThis retrospective cohort study included 400 rheumatological patients treated with TNFi and 400 healthy blood donors. Plasma samples were retrieved from the Danish Rheumatological Biobank and the Danish Blood Donor Study between 2015 and 2022. Age, sex, diagnosis and duration of TNFi treatment were recovered from the Danish Rheumatological Database, DANBIO. Data on age and sex were available for the blood donors. One plasma sample per individual was tested for N. mikurensis DNA-specific real-time PCR targeting the groEL gene.ResultsIn the rheumatological patients, the median age was 61 years (IQR 55–68 years), 62% were women, and 44% had a diagnosis of seropositive rheumatoid arthritis. In total, 54% of the patients were treated with infliximab. The median time from TNFi initiation to blood sampling was 20 months (IQR, 5–60 months). N. mikurensis DNA was not detected in any samples from patients or blood donors.ConclusionN. mikurensis infection does not appear to represent a prevalent risk in Danish rheumatological patients receiving TNFi or in blood donors.
We aimed to describe the use and findings of cranial computerized tomography (CT-head), spine and brain magnetic resonance imaging (MRI-spine/MRI-brain) in Lyme neuroborreliose (LNB).
Patients with ...LNB were identified using a nationwide, population-based prospective cohort of all adults treated for neuroinfections at departments of infectious diseases in Denmark from 2015 to 2019. Multivariate logistic regression analyses assessed associations between clinical characteristics and MRI-findings consistent with LNB.
We included 368 patients (272 definite LNB and 96 probable LNB), 280 scans were performed in 198 patients. Neuroimaging was associated with older age (59 vs. 57, p = 0.03), suspicion of other diseases (77% vs. 37%, p < 0.0001), no history of tick bites (58% vs. 43%, p = 0.01), physical/cognitive deficits prior to admission (15% vs 5%, p = 0.006), peripheral palsy (10% vs. 2%, p = 0.0008), encephalitis (8% vs. 1%, p = 0.0007) and cognitive impairment (8% vs. 2%, p = 0.03) compared with those without neuroimaging.
Normal or incidental findings were common (93/98 CT-head and 154/182 MRI). 1/98 CT-head, 19/131 MRI-brain and 6/51 MRI-spine had findings consistent with LNB.
Symptoms ≥45 days was associated with MRI-findings consistent with LNB (adjusted odds ratio (aOR) 4.2, 95%confidence interval 1.2–14.4, p = 0.02).
In this Danish cohort including 368 LNB-patients, use of neuroimaging was common and often performed in older comorbid patients without previous tick-bite intended to investigate alternative diagnoses. The results were in general without pathology and neuroimaging cannot exclude LNB or replace lumbar puncture. MRI is of value when investigating alternative neurological diseases and may support suspicion of LNB in cases with meningeal/leptomeningeal/neural enhancement.
•Most patients with Lyme neuroborreliosis have neuroimaging without pathology.•MRI enhancement of meninges or nerves is consistent with Lyme neuroborreliosis.•More than half of patients with Lyme neuroborreliosis have neuroimaging performed.•Neuroimaging often investigate alternative diagnoses in older comorbid patients.
We present a case demonstrating the performance of different radiographical and nuclear medicine imaging modalities in the diagnostic work-up of a patient with Lyme neuroborreliosis. The patient ...presented in late summer 2019 with radicular pains followed by a foot drop and peripheral facial palsy, both right-sided. Due to a history of breast cancer, disseminated malignant disease was initially suspected. Bone metastasis was ruled out by skeletal scintigraphy. Magnetic resonance imaging (MRI) of the neuroaxis and a whole body
F-FDG PET-CT was performed within 48 hours. The MRI revealed a strong contrast enhancement of the conus medullaris and fibers of the cauda equina, while the
F-FDG PET/CT was without pathological findings. Examination of cerebrospinal fluid led to the definitive diagnosis of Lyme neuroborreliosis with monocytic pleocytosis and a positive intrathecal test for
. The patient became pain-free after 10 days of ceftriaxone, and the paralysis slowly regressed the following month. This case highlights the difficulty of the diagnosis of Lyme neuroborreliosis and discusses the relevant imaging findings.
To provide better care for patients suspected of having a tick-transmitted infection, the Clinic for Tick-borne Diseases at Rigshospitalet, Copenhagen, Denmark was established. The aim of this ...prospective cohort study was to evaluate diagnostic outcome and to characterize demographics and clinical presentations of patients referred between the 1st of September 2017 to 31st of August 2019.
A diagnosis of Lyme borreliosis was based on medical history, symptoms, serology and cerebrospinal fluid analysis. The patients were classified as definite Lyme borreliosis, possible Lyme borreliosis or post-treatment Lyme disease syndrome. Antibiotic treatment of Lyme borreliosis manifestations was initiated in accordance with the national guidelines. Patients not fulfilling the criteria of Lyme borreliosis were further investigated and discussed with an interdisciplinary team consisting of specialists from relevant specialties, according to individual clinical presentation and symptoms. Clinical information and demographics were registered and managed in a database.
A total of 215 patients were included in the study period. Median age was 51 years (range 17–83 years), and 56 % were female. Definite Lyme borreliosis was diagnosed in 45 patients, of which 20 patients had erythema migrans, 14 patients had definite Lyme neuroborreliosis, six had acrodermatitis chronica atrophicans, four had multiple erythema migrans and one had Lyme carditis. Furthermore, 12 patients were classified as possible Lyme borreliosis and 12 patients as post-treatment Lyme disease syndrome. A total of 146 patients (68 %) did not fulfil the diagnostic criteria of Lyme borreliosis. Half of these patients (73 patients, 34 %) were diagnosed with an alternative diagnosis including inflammatory diseases, cancer diseases and two patients with a tick-associated disease other than Lyme borreliosis. A total of 73 patients (34 %) were discharged without sign of somatic disease. Lyme borreliosis patients had a shorter duration of symptoms prior to the first hospital encounter compared to patients discharged without a specific diagnosis (p<0.001). When comparing symptoms at presentation, patients discharged without a specific diagnosis suffered more often from general fatigue and cognitive dysfunction.
In conclusion, 66 % of all referred patients were given a specific diagnosis after ended outpatient course. A total of 32 % was diagnosed with either definite Lyme borreliosis, possible Lyme borreliosis or post-treatment Lyme disease syndrome; 34 % was diagnosed with a non-tick-associated diagnosis. Our findings underscore the complexity in diagnosing Lyme borreliosis and the importance of ruling out other diseases through careful examination.
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