AbstractObjectiveTo estimate long term survival, health, and educational/social functioning in patients with Lyme neuroborreliosis compared with the general population.DesignNationwide population ...based cohort study using national registers.SettingDenmark.ParticipantsAll Danish residents diagnosed during 1986-2016 as having Lyme neuroborreliosis (n=2067), defined as a positive Borrelia burgdorferi intrathecal antibody test and a clinical diagnosis of Lyme borreliosis, and a comparison cohort from the general population matched on sex and date of birth (n=20 670).Main outcome measuresMortality rate ratios, incidence rate ratios of comorbidities, and differences in educational and social outcomes.ResultsMortality among patients with Lyme neuroborreliosis was not higher than in the general population (mortality rate ratio 0.90, 95% confidence interval 0.79 to 1.03). Lyme neuroborreliosis patients had increased risk of haematological (incidence rate ratio 3.07, 2.03 to 4.66) and non-melanoma skin cancers (1.49, 1.18 to 1.88). At diagnosis, Lyme neuroborreliosis patients had slightly higher employment and lower disability pension rates. After five years, patients and comparison cohort members had similar numbers of hospital contacts (difference −0.22, 95% confidence interval −0.45 to 0.02, in-hospital days/year; 0.37, −0.10 to 0.83, outpatient visits/year), employment rates (difference 1.5%, −2.1% to 5.1%), income (difference −1000, −20 000 to 18 000, Danish kroner), days of sick leave (difference −0.3, −3.5 to 3.0, per year), rates of receipt of a disability pension (difference −0.9%, −3.2% to 1.3%), and number of children (difference –0.10, −0.27 to 0.08). More patients were married (difference 4.8%, 2.2% to 7.4%) and had completed high school education (difference 7%, 1% to 12%).ConclusionA verified diagnosis of Lyme neuroborreliosis had no substantial effect on long term survival, health, or educational/social functioning. Nevertheless, the diagnosis decreased labour market involvement marginally and was associated with increased risk of haematological and non-melanoma skin cancers.
Abstract
Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the ...cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood–brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50 g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood–brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18–264.96; P = 0.04; n = 15. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood–brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood–brain barrier are more likely to contribute to neuro-COVID.
CSF was analysed from 38 neuro-COVID patients. None had SARS-CoV-2 RNA in CSF. Forty-four per cent exhibited CSF anti-spike SARS-CoV-2 antibodies without signs of intrathecal synthesis, but antibody levels correlated strongly with blood–brain barrier permeability. CSF anti-neuronal autoantibodies were not detected. Therefore, critical illness and peripheral inflammation contribute mostly to neuro-COVID.
Graphical Abstract
Graphical Abstract
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.
Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce.
...Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark.
We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1–10.4)).
PLWH with NS have better outcomes than NS patients without HIV infection.
Encephalitis caused by Borrelia burgdorferi sensu lato is a rare clinical manifestation of Lyme neuroborreliosis and only in few cases have brain parenchymal inflammation been documented. Here, we ...present a case of Lyme neuroborreliosis with encephalitis with significant parenchymal inflammation on magnetic resonance imaging (MRI) in an immunosuppressed patient.
•We here report a rare case of Lyme neuroborreliosis with encephalitis.•The patient was immunosuppressed and presented with uncharacteristic symptoms.•Magnetic Resonance imaging showed significant parenchymal changes.•Early diagnosis of this treatable infection is of great importance.
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.
•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.
Summary
Objective
To investigate the development of lung function in HIV‐infected patients.
Methods
In a prospective cohort study, 88 HIV‐infected patients had a lung function test performed and 63 ...patients (72%) had their LFT repeated with a median follow‐up period of 4·4 years. Forty‐eight per cent were smokers, and at the re‐examination, 97% were on combination antiretroviral therapy.
Results
Carbon monoxide diffusion capacity was reduced and decreased over time in both smokers and non‐smokers. Alveolar volume decreased and forced vital capacity increased similarly in both smokers and non‐smokers. No changes were observed in forced expiratory volume or peak flow, but smokers had reduced values compared with those of the non‐smokers at both examinations. FEV1/FVC was reduced especially in smokers and declined in both smokers and non‐smokers.
Conclusions
Carbon monoxide diffusion capacity is reduced in HIV‐infected patients and seems to decline over time. Additionally, signs of obstructive lung disease are present in HIV‐infected patients and seem to increase over time, although only modestly.
BackgroundPre-exposure prophylaxis (PrEP) effectively prevents HIV, but its association with sexually transmitted infections (STIs) has raised concerns about risk compensation, potentially impacting ...the expansion of PrEP programmes.AimWe examined the relationship between PrEP and the incidence of chlamydia, gonorrhoea and syphilis.MethodsIn this prospective cohort study, we compared STI rates before and after PrEP initiation among users in the capital region of Denmark (2019-2022), calculating incidence rate ratios adjusted for age and testing frequency (aIRR). To pinpoint when increases began, we plotted weekly STI rates, adjusting the timeline to correspond with PrEP initiation.ResultsThe study included 1,326 PrEP users with a median age of 35 years. The STI incidence rate per 100,000 person-years rose from 35.3 before to 81.2 after PrEP start, with an aIRR of 1.35 (95% CI: 1.18-1.56). Notably, this increase preceded PrEP initiation by 10-20 weeks. Specific aIRR for chlamydia, gonorrhoea and syphilis were 1.23 (95% CI: 1.03-1.48), 1.24 (95% CI: 1.04-1.47) and 1.15 (95% CI: 0.76-1.72), respectively. In subanalyses for anatomical sites aIRR was 1.26 (95% CI: 1.01-1.56) for rectal chlamydia and 0.66 (95% CI: 0.45-0.96) for genital gonorrhoea.ConclusionWe found a 35% increase in STI incidence associated with PrEP use. It started before PrEP initiation, challenging the assumption that PrEP leads to risk compensation. Instead, the data suggest that individuals seek PrEP during periods of heightened sexual risk-taking. Consequently, PrEP programmes should include sexual health consultations, STI testing, treatment and prevention strategies to prevent HIV and improve sexual health.
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.
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