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Background. Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis. Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications. Methods. One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned to placebo (n = 51) or 0.5 g of valacyclovir twice daily (n = 50) for 1 year after initial treatment with 1 g of valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome was time until recurrence of meningitis. The patients were followed up for 2 years. Results. The first year, no significant difference was found between the valacyclovir and placebo groups. The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.06-10.21]). One-third of the patients experienced 1-4 meningitis episodes during the study period. A considerable morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was found in both groups. Conclusions. Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could be interpreted as a rebound phenomenon. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to characterise long-term neurological and neurocognitive sequelae after tick-borne encephalitis (TBE) in adults., Methods: 98 prospective consecutive TBE patients, classified by disease severity, were included. Immediate outcomes were evaluated with Glasgow Outcome Scale (GOS) and Rankin Scale (RS). After 6 and 18 months, long-term disability was evaluated using Modified Rankin Scale (MRS) and neurocognitive assessment was performed with Matrics Consensus Cognitive Battery (MCCB), measuring processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving and social cognition. The MCCB results were compared to healthy age, gender and education-matched controls., Results: Mild, moderate, and severe TBE was diagnosed in 53.1%, 38.8%, and 8.2% of cases, respectively. At discharge, 25.5% of the patients had major or moderate impairments (GOS) and various levels of disability in 34.7% (RS). Up to 18 months from the onset of TBE, over 20% remained with slight to moderate disability (MRS). GOS, RS and MRS scores correlated with disease severity. At 6 months after the onset, TBE patients scored significantly lower than controls in processing speed, verbal, and visual learning. Two latter domains were significantly more impaired in patients with mild TBE. Patients aged 18-39 performed significantly worse in attention/vigilance and working memory, whereas aged 60+ in verbal learning. A year later, significant improvement was observed in six of seven cognitive domains., Conclusions: Long-term neurological sequelae persist in a substantial proportion of TBE patients with significant impairment in several cognitive domains, especially in younger patients and even after mild TBE.

Background: Human parechovirus (HPeV) infections can cause sepsis and meningoencephalitis in infants. To improve our knowledge of the consequences of HPeV infections in young children, the incidence, clinical spectrum, and short-term outcome among infants infected with HPeV were investigated retrospectively., Methods: The presence of HPeV RNA was investigated by polymerase chain reaction in cerebrospinal fluid from 327 children aged 0 to 12 months sampled between 2014 and 2017. Eighty-one were infected with HPeV and included in the study. These infants were divided into 3 groups based on clinical assessment: HPeV was the presumed cause of disease (n = 35); HPeV could have contributed to or been considered the cause of disease (n = 24); and HPeV was not considered the cause of disease (n = 22)., Results: Infection with HPeV type 3 was common in all groups (n = 54), and most children were younger than 3 months (n = 63). The children in the first group (HPeV as presumed cause) had meningoencephalitis (n = 20), viral sepsis (n = 9), or non-severe viral infection (n = 6). The youngest were more prone to develop meningoencephalitis, while the slightly older children had symptoms of viral sepsis or nonsevere viral infection ( P < .05). Eleven had symptom onset within 2 days after birth. Two infants diagnosed with sudden infant death syndrome were HPeV infected when tested postmortem., Conclusions: HPeV infections were identified in 25% of children with suspected central nervous system infection. The clinical presentation of those infected with HPeV varied with age. HPeV infections may be associated with sudden infant death syndrome, although this is not well studied. The results suggest that HPeV infections may be underdiagnosed in young infants., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Importance: Antibiotic treatment saves lives in newborns with early-onset sepsis (EOS), but unwarranted antibiotic use is associated with resistant bacteria and adverse outcomes later in life. Surveillance is needed to optimize treatment strategies., Objective: To describe antibiotic use in association with the incidence and mortality from EOS among late-preterm and full-term newborns., Design, Setting, and Participants: The Sweden Neonatal Antibiotic Use study was a nationwide observational study that included all late-preterm and full-term neonates born from January 1, 2012, to December 31, 2020, in neonatal units of all levels. All hospital live births from 34 weeks' gestation during the study period were included in the study. Data were collected from the Swedish Neonatal Quality Register and the Swedish Medical Birth Register. Data were analyzed from August 2022 to May 2023., Exposure: Admission for neonatal intensive care during the first week of life., Main Outcomes and Measures: The main outcomes were the usage of intravenous antibiotics during the first week of life, the duration of antibiotic therapy, the rate of culture-proven EOS, and mortality associated with EOS., Results: A total of 1 025 515 newborns were included in the study; 19 286 neonates (1.88%; 7686 girls [39.9%]; median [IQR] gestational age, 40 [38-41] weeks; median [IQR] birth weight, 3610 [3140-4030] g) received antibiotics during the first week of life, of whom 647 (3.4%) had EOS. The median (IQR) duration of antibiotic treatment in newborns without EOS was 5 (3-7) days, and there were 113 antibiotic-days per 1000 live births. During the study period there was no significant change in the exposure to neonatal antibiotics or antibiotic-days per 1000 live births. The incidence of EOS was 0.63 per 1000 live births, with a significant decrease from 0.74 in 2012 to 0.34 in 2020. Mortality associated with EOS was 1.39% (9 of 647 newborns) and did not change significantly over time. For each newborn with EOS, antibiotic treatment was initiated in 29 newborns and 173 antibiotic-days were dispensed., Conclusions and Relevance: This large nationwide study found that a relatively low exposure to antibiotics is not associated with an increased risk of EOS or associated mortality. Still, future efforts to reduce unwarranted neonatal antibiotic use are needed.

Background: To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC)., Methods: Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed., Results: SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies., Conclusions: We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation., Competing Interests: Potential conflicts of interest . K. B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; served at data monitoring committees for Julius Clinical, and Novartis; given lectures, produced educational materials, and participated in educational programs for Biogen, Eisai, and Roche Diagnostics; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H. Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). A. E. has received lecture honoraria from Gilead. M. G. has received research grants from Gilead Sciences and honoraria as speaker, DSMB committee member, and/or scientific advisor from Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer, and Sanofi. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Cancer treatment with immune checkpoint inhibition (ICI) can cause immune-related adverse events in the central nervous system (CNS irAE). There are no blood biomarkers to detect CNS irAE. We investigated if concentrations of S100-calcium-binding protein B (S100B) and neurofilament light chain (NfL) in blood can be used as biomarkers for CNS irAE and assessed the incidence of CNS irAE in a cohort of ICI-treated patients., Methods: In this single-centre, retrospective cohort study, we examined medical records and laboratory data of 197 consecutive patients treated with combined CTLA-4 and PD-1 inhibition (ipilimumab; ipi + nivolumab; nivo) for metastatic melanoma or renal cell carcinoma. CNS irAE was diagnosed using established criteria. Concentrations of S100B and NfL in blood were measured in patients with CNS irAE and in 84 patients without CNS irAE., Findings: Nine of 197 patients (4.6%) fulfilled criteria for CNS irAE. S100B and NfL in blood increased during CNS inflammation and normalized during immunosuppression. CNS irAE was detected with a sensitivity of 100% (S100B) and 79% (NfL) and a specificity of 89% (S100B) and 74% (NfL). Patients with CNS irAE had simultaneous increased concentration of C-reactive protein (CRP) (9/9) and alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) in blood (8/9)., Interpretation: Analysis of S100B, NfL and CRP in blood facilitates the diagnosis of CNS irAE. CNS irAE may be more common than previously reported. There may be shared immune mechanisms between CNS and hepatitis irAE., Funding: Supported by funding from the Swedish Cancer Foundation, the ALF-agreement, and Jubileumsklinikens Cancerfond., Competing Interests: Declaration of interests SB has received lecturing fees from Bristol Myers Squibb. ML has received lecturing fees from Bristol Myers Squibb, MSD, Roche, and Novartis. LN has received lecturing fees from Bristol Myers Squibb, Glaxo Smith Kline, MSD, Novartis, and Pierre Fabre. LN has received advisory board fees from Bristol Myers Squibb, Glaxo Smith Kline, MSD, Novartis, Pierre Fabre and Zealth. LN has stocks/ownership in SATMEG Ventures. HZ has received consulting or advisory board fees from Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave. HZ has received lecturing fees from Fujirebio, Alzecure, Cellectricon, Biogen and Roche. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program. The other authors report no disclosures., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-β1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway. The patient allele encoded a truncated IKKε protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell-derived microglia, HSV-2-induced expression of IFNB1 was dependent on cGAS, TANK binding kinase 1 (TBK1), and IKBKE, but not TLR3, and supernatants from HSV-2-treated microglia exerted IKBKE-dependent type I IFN-mediated antiviral activity upon neurons. Reintroducing wild-type IKBKE into patient cells rescued IFNB1 induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKKε to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS/STING pathway in human antiviral immunity.

Objectives: We examined the temporal changes of the CSF proteome in patients with herpes simplex encephalitis (HSE) during the course of the disease, in relation to anti-N-methyl-D-aspartate receptor (NMDAR) serostatus, corticosteroid treatment, brain MRI and neurocognitive performance., Methods: Patients were retrospectively included from a previous prospective trial with a pre-specified CSF sampling protocol. Mass spectrometry data of the CSF proteome were processed using pathway analysis., Results: We included 48 patients (110 CSF samples). Samples were grouped based on time of collection relative to hospital admission - T1: ≤ 9 d, T2: 13-28 d, T3: ≥ 68 d. At T1, a strong multi-pathway response was seen including acute phase response, antimicrobial pattern recognition, glycolysis and gluconeogenesis. At T2, most pathways activated at T1 were no longer significantly different from T3. After correction for multiplicity and considering the effect size threshold, 6 proteins were significantly less abundant in anti-NMDAR seropositive patients compared to seronegative: procathepsin H, heparin cofactor 2, complement factor I, protein AMBP, apolipoprotein A1 and polymeric immunoglobulin receptor. No significant differences in individual protein levels were found in relation to corticosteroid treatment, size of brain MRI lesion or neurocognitive performance., Conclusions: We show a temporal change in the CSF proteome in HSE patients during the course of the disease. This study provides insight into quantitative and qualitative aspects of the dynamic pathophysiology and pathway activation patterns in HSE and prompts for future studies on the role of apolipoprotein A1 in HSE, which has previously been associated with NMDAR encephalitis.

Background and Purpose: Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis., Methods: One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate or severe tick-borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL-40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere-Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test was used to adjust for age., Results: Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL-40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity., Conclusions: Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick-borne encephalitis, and future studies should focus on determining the association between these biomarkers and long-term sequelae., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

In 2015, an outbreak caused by OXA-48-producing Enterobacteriaceae affected a neonatal intensive care unit at a Swedish University Hospital. The aim was to explore the transmission of OXA-48-producing strains between infants and the transfer of resistance plasmids between strains during the outbreak. Twenty-four outbreak isolates from ten suspected cases were whole-genome sequenced. A complete assembly was created for the index isolate (Enterobacter cloacae) and used as a mapping reference to detect its plasmids in the remaining isolates (17 Klebsiella pneumoniae, 4 Klebsiella aerogenes, and 2 Escherichia coli). Strain typing was performed using core genome MLST and SNP analysis. As judged from sequencing and clinical epidemiological data, the outbreak involved nine cases (two developed sepsis) and four OXA-48-producing strains: E. cloacae ST1584 (index case), K. pneumoniae ST25 (eight cases), K. aerogenes ST93 (two cases), and E. coli ST453 (2 cases). Two plasmids from the index strain, pEclA2 and pEclA4, carrying bla OXA48 and bla CMY-4 , respectively, were traced to all K. pneumoniae ST25 isolates. Klebsiella aerogenes ST93 and E. coli ST453 harboured either only pEclA2, or both pEclA2 and pEclA4. One suspected case harbouring OXA-162-producing K. pneumoniae ST37 could be excluded from the outbreak. Once initiated by an E. cloacae strain, the outbreak was caused by the dissemination of a K. pneumoniae ST25 strain and involved inter-species horizontal transfer of two resistance plasmids, one of which carried bla OXA-48 . To our knowledge, this is the first description of an outbreak of OXA-48-producing Enterobacteriaceae in a neonatal setting in northern Europe., (© 2023. The Author(s).)

Tick-borne encephalitis (TBE) is a viral disease endemic in Eurasia. The virus is mainly transmitted to humans via ticks and occasionally via the consumption of unpasteurized milk products. The European Centre for Disease Prevention and Control reported an increase in TBE incidence over the past years in Europe as well as the emergence of the disease in new areas. To better understand this phenomenon, we investigated the drivers of TBE emergence and increase in incidence in humans through an expert knowledge elicitation. We listed 59 possible drivers grouped in eight domains and elicited forty European experts to: (i) allocate a score per driver, (ii) weight this score within each domain, and (iii) weight the different domains and attribute an uncertainty level per domain. An overall weighted score per driver was calculated, and drivers with comparable scores were grouped into three terminal nodes using a regression tree analysis. The drivers with the highest scores were: (i) changes in human behavior/activities; (ii) changes in eating habits or consumer demand; (iii) changes in the landscape; (iv) influence of humidity on the survival and transmission of the pathogen; (v) difficulty to control reservoir(s) and/or vector(s); (vi) influence of temperature on virus survival and transmission; (vii) number of wildlife compartments/groups acting as reservoirs or amplifying hosts; (viii) increase of autochthonous wild mammals; and (ix) number of tick species vectors and their distribution. Our results support researchers in prioritizing studies targeting the most relevant drivers of emergence and increasing TBE incidence.

Importance: Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF)., Objective: To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity., Design, Setting, and Participants: This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, β2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL])., Results: Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, β2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease., Conclusions and Relevance: In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.

In recent decades, the incidence of tick-borne encephalitis (TBE) in Sweden has increased. To calculate the burden of disease over a 17-year period, we analyzed data from the Swedish National Health Data Register for TBE cases diagnosed during 1998-2014. We compared healthcare use and sick leave associated with 2,429 persons with TBE with a referent cohort of 7,287 persons without TBE. Patients with TBE were hospitalized for significantly more days during the first year after disease onset (11.5 vs. 1.1 days), logged more specialist outpatient visits (3.6 vs. 1.2 visits), and logged more sick leave days (66 vs. 10.7 days). These differences generally increased over time. The case-fatality rate for TBE was 1.1%. Our calculated cost of TBE to society provides a baseline for decisions on immunization programs. Analyzing register data, our study adds to clinical studies of smaller cohorts and model-based studies that calculate disease burden.

Objectives: In central nervous system infections, early and correct management is of utmost importance. Rapid syndromic panel testing can potentially provide valuable guidance. The FilmArray meningitis/encephalitis (ME) panel detects 14 pathogens through multiplex PCR. Our study objectives were to assess its performance compared with established diagnostic procedures, especially real-time quantitative PCR for detection of viruses, and to determine the diagnostic and clinical significance of discrepant results., Methods: All cerebrospinal fluid samples sent for viral diagnostics to our microbiological laboratory over 34 months were analysed with the ME panel and in-house real-time PCR for herpes simplex virus type 1 (HSV-1), HSV-2, varicella zoster virus and enteroviruses. Other pathogens detected by the panel were confirmed by routine diagnostic procedures. Discrepant results were analysed through interpretation of biological and clinical data, and performance data were calculated for individual pathogens., Results: Altogether, 315 pathogens were detected by the ME panel in 4199 cerebrospinal fluid samples (7.5%) and an additional 21 viral targets were identified using real-time PCR. Thirty-four ME panel detections were not confirmed, totalling 55 discrepant results. After discrepancy analysis, 20 false-positive and 21 false-negative ME panel results remained. Performance varied between pathogens. Sensitivity for HSV-1 was calculated at 82.4% (59.0%-93.8%) with three false-negative results. Also noteworthy were 13 false-negative enterovirus and eight false-positive Streptococcus pneumoniae results., Conclusions: Our analysis shows good performance for the ME panel in diagnosing central nervous system infection. The risk of false-negative HSV-1 results, however, warrants additional testing when encephalitis is suspected. Uncertainties in interpretation of enterovirus and S. pneumoniae results represent other limitations., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aim was to investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE)., Methods: A total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/cerebrospinal fluid (CSF) sampling and brain magnetic resonance imaging in the first 3 months along with cognitive assessment using the Mattis Dementia Rating Scale (MDRS) at 24 months. CSF samples were analysed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The predefined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months., Results: Impaired cognitive performance significantly correlated with NFL levels (rho = -0.36, p = 0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-N-methyl-D-aspartate receptor (NMDAR) (beta = -0.6249, p = 0.024) and age (z-score beta = -0.2784, p = 0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006)., Discussion: Our findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Our aim was to assess response and side effects of 4 doses of TBE vaccine to patients (pts) after allo- and autologous stem cell transplantation (SCT)., Patients: Included were 104 pts with leukaemia, myeloma and lymphoma, median age 61 yrs., Methods: Vaccine (FSME-Immun®) was given at 9, 10, 12, and 21 months post-transplant. Serum samples were obtained before and after vaccinations. Healthy controls (n = 27) received 3 vaccinations. Assessments of TBE specific IgG antibodies were performed by Enzygnost anti-TBE ELISA test (Siemens, Sweden)., Results: Antibody levels (>12 U/mL; "seropositivity") were seen in 77% and 80% of pts after allo- and autoSCT; IgG levels; 89 vs 94 U/mL. Ongoing chronic GvHD and immunosuppression (n = 29) was associated with sero-negativity in the last sample (p = 0.007). All controls (n = 27) developed protective antibody levels., Conclusions: TBE vaccination was safe, and 4 doses starting 9 months post-SCT, induced seropositivity in a vast majority of pts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tick-borne encephalitis (TBE) is a widespread viral infection of the central nervous system with increasing incidence in Europe and northern Asia. Post-infectious sequelae are frequent, and patients with TBE commonly experience long-term fatigue and subjective sleep disturbances. Obstructive sleep apnea (OSA) may be a contributing factor, and objective sleep studies with polysomnography (PSG) are lacking. Forty-two adults, 22 TBE patients (cases), diagnosed in Region Västra Götaland, Sweden, between 2012 and 2015, and 20 controls without a known TBE history, underwent an overnight PSG, respectively. All participants responded to questionnaires. The cases and controls were similar regarding age, sex, obesity, concomitant diseases, smoking, and alcohol habits. Despite similar PSG characteristics such as total sleep time and OSA severity indices, the TBE cases reported statistically more sleep-related functional impairment on the Functional Outcome of Sleep Questionnaire (FOSQ) compared with the controls (median scores 18.1 vs. 19.9; p<0.05). In a multivariate analysis, TBE correlated significantly with the lower FOSQ scores (unstandardized β -1.80 [%95 confidence interval -3.02 - -0.58]; p = 0.005) independent of age, sex, total sleep time and apnea-hypopnea-index. TBE cases with OSA reported the lowest scores on the FOSQ compared with the other subgroups with TBE or OSA alone, and the ones with neither TBE nor OSA. TBE is associated with impaired functional outcomes, in which concomitant OSA may worsen the subjective symptoms. Further studies are warranted to determine the effect of treatment of concomitant OSA on functional outcomes with regard to optimal rehabilitation of TBE., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Excessive administration of antibiotics to preterm infants is associated with increased rates of complications. The purpose of the study was to evaluate the effect of an antimicrobial stewardship intervention on antibiotic use in extremely preterm infants., Design Setting Patients and Intervention: A before and after study of infants born at ≤28 weeks' gestational age was performed in the neonatal intensive care unit of Queen Silvia's Children's Hospital, Gothenburg, Sweden. Retrospective analysis of the baseline period (January-December 2014) guided the development of a limited antimicrobial stewardship intervention. The intervention consisted of updated local guidelines with a focus on shortened and standardised treatment duration plus increased access to infectious disease consultant advice. It was fully implemented during the intervention period (October 2017-September 2018)., Objective: Primary aim was to compare antibiotic use, defined as antibiotic treatment days per 1000 patient-days, between the two periods, and the secondary aim was to evaluate the number of days with meropenem-based regimens before and after the intervention., Results: We included 145 infants with a median birth weight of 870 g and median gestational age of 26 weeks. The baseline period comprised 82 infants and 3478 patient-days, the intervention period comprised 63 infants and 2753 patient-days. Overall antibiotic use (treatment and prophylaxis) was 534 versus 466 days per 1000 patient-days during the baseline and intervention periods, respectively. Antibiotic treatment days decreased from 287 to 197 days per 1000 patient-days. The proportion of meropenem-based regimens was 69% versus 44%, respectively. No increases in mortality or reinitiation of antibiotics were seen., Conclusions: Implementation of a limited antimicrobial stewardship intervention anchored in analysis of previous prescription patterns can contribute to safe decreases in antibiotic use in extremely preterm infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early-onset sepsis (EOS) is a potentially life-threatening complication of birth. Clinical symptoms are often unspecific and biomarkers have low predictive values for EOS. Therefore, clinical suspicion often leads to antibiotic therapy in neonates with a negative blood culture. In the study we evaluated if a quality improvement initiative could reduce unwarranted antibiotic use in a safe way in term neonates with culture-negative sepsis., Methods: The quality improvement initiative included new treatment guidelines and were introduced on 11 June 2018. The guidelines included C-reactive protein- and clinical symptoms-guided decision-making and shorter intravenous antibiotic therapy. All term neonates treated for EOS at Ryhov Hospital, Jönköping, Sweden were studied before (period 1: 2016-2017) and after the introduction of the new guidelines (period 2: 11 June 2018 to 30 Sept 2019). Laboratory and clinical data were analysed., Results: There were 7618 term neonates in period 1 and 5005 term neonates in period 2. We identified 140 (1.8%) EOS in period 1 and 97 (1.9%) EOS in period 2. During period 1 and 2, there were 61 (61/140, 44%) and 59 (59/97, 61%) EOS neonates, respectively, who met the criteria for shorter antibiotic treatment. The number of positive blood cultures were seven (0.92/1000 live births) and five (1.0/1000 live births) in period 1 and 2. The median C-reactive protein were 52 mg/L (37-62) in period 1 and 42 mg/L (31-56) in period 2 in the group who met the criteria of the guidelines. The duration of antibiotic therapy (Median: seven vs. five days, p < 0.001) and hospital stay (Median: seven vs. five days, p < 0.001) as well as healthcare costs (decreased by €122,000/year) was reduced in the group who met the criteria after the introduction of the guidelines., Conclusion: C-reactive protein- and clinical symptoms-guided decision-making for EOS significantly decreased the duration of antibiotic therapy and hospital stay, and hence reduced healthcare costs, with no reinfection in a cohort of term infants., Trial Registration: Trial registration number: ISRCTN29535824 . Date of registration: 28 May 2020. Retrospectively registered.

Background: Staphylococcus aureus bacteraemia (SAB) is recognized as an infection that is difficult to treat and with high risk of device related infection. Extraction/explantation of cardiac implantable electronic devices (CIED) is recommended in SAB patients but studies evaluating long-term prognosis are scarce., Materials and Methods: In this retrospective cohort study, 626 consecutive SAB patients were identified in routine diagnostics (November 2014-October 2016). Patient characteristic, infective endocarditis (IE) incidence and mortality were compared for patients with and without CIED., Results: SAB patients with CIED ( n  = 33) compared to non-CIED patients ( n  = 593) were older (83 versus 70 years, p  = .0001), had a higher 30-day mortality (12/33, 36% versus 119/593, 20%, p  = .044) and higher incidence of IE (9/33, 27% versus 41/593, 7%, p  = .0006). One-year mortality was 19/33 (58%) among the SAB CIED patients. Echocardiography was performed in all nine patients with CIED-IE but only in 14/24 (58%) of the 24 SAB CIED patients that were considered not having IE. However, if patients with very early mortality were excluded, echocardiography was performed in 14/17 (82%) of SAB CIED-non-IE patients. CIED extraction/explantation during intravenous antibiotic treatment was only performed in three patients with SAB CIED-IE and in one non-IE patient. One year post treatment initiation, 14 out of 33 SAB CIED patients were alive of whom only one had CIED extraction/explantation performed as part of treatment., Conclusion: Staphylococcus aureus bacteraemia in CIED patients is associated with poor prognosis but in a subgroup of patients survival beyond one year was seen despite retainment of the electronic device.

Background: Few studies have focused on the treatment of tuberculosis (TB) during pregnancy. This study aimed to evaluate the risk of adverse events, particularly liver toxicity, in pregnant women during treatment for active TB., Methods: We conducted a retrospective study on pregnant and age-matched non-pregnant women receiving treatment for active TB at four hospitals in Western Sweden between 1992 and 2017., Results: A total of 135 women were included, 40 pregnant and 95 non-pregnant. The frequency of severe hepatotoxicity was 40% in pregnant women and 6% among non-pregnant women (p < 0.001) (odds ratio 9.9; 95% confidence interval 3.5-28.0). Temporary drug withdrawal due to elevated transaminase levels was more frequent for pregnant than non-pregnant women (40% vs 9.5%; p < 0.001) (odds ratio 6.4; 95% confidence interval 2.5-16.2). There was one fatal case of hepatotoxicity in a pregnant woman., Conclusion: Severe hepatotoxicity was significantly more frequent in pregnant women compared to non-pregnant women. Careful monitoring of liver transaminases while receiving TB treatment during pregnancy is mandatory, as well as ensuring adequate measures with adjustment of drug regimen and temporary drug withdrawals when a rise in liver enzymes is noted., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

High cerebrospinal fluid (CSF) concentrations of the chemokine CXCL13 have been associated with Lyme neuroborreliosis (LNB), and have recently been studied as a potential diagnostic marker. It has proven difficult to establish a reliable diagnostic cut-off, possibly in part due to heterogenicity of case-control groups. Our purpose was to investigate CSF CXCL13 concentrations in patients with similar clinical presentations, facial palsy. We retrospectively included patients with facial palsy associated with LNB (n = 21), or varicella zoster virus (VZV) (n = 26). Median CXCL13 concentrations were significantly higher in patients with LNB facial palsy compared to VZV facial palsy. Receiver-operating characteristic analyses yielded an optimal cut-off concentration at 34.5 pg/mL (sensitivity 85.7%, specificity of 84.6%), lower than that in previous studies. Although the analysis has potential, it is still not adequately established that CXCL13 provides additional, clinically useful, diagnostic information over current recommendations., Competing Interests: Declaration of competing interest HZ has served at scientific advisory boards for Roche Diagnostics, Samumed, CogRx and Wave, has given lectures in symposia sponsored by Biogen and Alzecure, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg (all outside submitted work). KB has served as a consultant or at advisory boards for Biogen, Lilly, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, (all outside submitted work). The other authors report no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Tick-borne encephalitis (TBE) is an emerging infectious disease in large parts of Europe and Asia. Whereas other members of the Flaviviridae family can harm fetal development, there are only very few reports on TBE virus (TBEV) infections during pregnancy. Thus, the implications for fetal health remain largely unknown. In this study, we present detailed pre- and postnatal health assessment of three children in the context of severe maternal TBEV infection during pregnancy. Following acute TBEV infection of the mothers, intrauterine growth and development of all children were assessed by repetitive prenatal ultrasound. Postnatal examinations included clinical and virological analyses over a follow-up period of 18 months. Prenatally, no signs of intrauterine growth restrictions were observed. All neonates were delivered at term. Umbilical cord blood of the newborns tested negative for TBEV RNA. Virus-specific IgG antibodies were positive at birth but negative at 9 and 11 months of age. Importantly, IgM antibodies remained negative throughout the period of observation. Taken together, these clinical and virological data strongly suggest that fetal TBEV infection did not occur, despite severe manifestations in the mothers., Competing Interests: Declaration of Competing Interest Dr. Dobler reports honoraria for lectures and fees for consulting by Pfizer Vaccines unrelated to the submitted work. Dr. Louwen reports personal fees from Nestlé and Milupa and non-financial support from the German Ministry of Health unrelated to the submitted work. Dr. Strzelczyk reports grants and/or personal fees from Desitin Arzneimittel, Eisai, GW pharmaceuticals, LivaNova, Marinus pharmaceuticals, Medtronic, Sage therapeutics, UCB pharma, Zogenix and Arvelle Therapeutics unrelated to the submitted work., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

On March 17, 2020, the Swedish Government recommended all higher education institutions to move to online and distance learning during the COVID-19 pandemic. The integrated course in Infection, Microbiology, and Immunity at the Programme in Medicine at University of Gothenburg had to be completely transformed. Creative solutions have now replaced the clinical training that normally takes place during the students' clinical education at the hospital. We developed a digital concept entitled "the virtual ward", in which we interact with the students in real time. Here, the students are able to follow their patients on a daily basis during teacher-guided sessions.

Background: Aciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood-brain barrier (BBB) in acute CNS infection may be of interest., Objectives: To investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS., Methods: We investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNS infection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical records were assessed retrospectively to identify patients with AINS., Results: Increased CSF:serum albumin ratio, as well as decreased renal function and high aciclovir doses, was associated with increased aciclovir and CMMG concentrations in the CSF. We identified five patients with new neuropsychiatric symptoms; four of those were considered to have AINS and had increased CSF CMMG concentrations. Only one patient without suspicion of AINS had an increased CSF CMMG concentration., Conclusions: In patients with herpesvirus CNS infections, BBB disruption is associated with increasing aciclovir and CMMG CSF concentrations. We also found an unexpectedly high number of patients with AINS. Evaluation of CSF:serum albumin ratios, renal function and CSF concentrations of aciclovir and CMMG may all contribute to the optimization of aciclovir dosing and avoidance of AINS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Tick-borne encephalitis (TBE) is one of the most prevalent viral central nervous system (CNS) infections in Eurasia and neurological sequelae are common. The immune responses are considered crucial for the pathogenesis. The aim of this study was to explore the activation of the complement system in TBE. The complement system is a part of the innate immune response in the CNS, which previously has been reported to be activated in other flavivirus infections. We analyzed complement factors in 44 paired cerebrospinal fluid (CSF) and serum samples from 20 cases of TBE in the acute and later stages, as well as in serum and CSF from 32 healthy controls. The concentrations of complement factors C1q, C3a, C3b, and C5a were determined with commercially available ELISA kits. Clinical data to categorize the severity of disease and outcome was retrieved from the medical records of the TBE patients. We found significantly higher concentrations of all of the analyzed complement factors in the CSF from TBE patients compared to the healthy controls. In particular, the marked increment of C1q concentrations in the CSF (p < 0,001 as compared to controls) indicated an intrathecal activation by the classical pathway. There was no correlation between complement factor concentrations in the CSF and severity of the disease in the acute phase or with sequelae at 6 months follow-up. We have found an intrathecal complement activation in TBE, and the marked increase of complement factor C1q indicated an activation by the classical pathway.

In an outbreak of measles in Gothenburg, Sweden, breakthrough infections (i.e. infections in individuals with a history of vaccination) were common. The objective of this study was to compare measles RNA levels between naïve (i.e. primary) and breakthrough infections. We also propose a fast provisional classification of breakthrough infections. Medical records were reviewed and real-time PCR-positive samples genotyped. Cases were classified as naïve, breakthrough or vaccine infections. We compared clinical symptoms and measles RNA cycle threshold (Ct) values between breakthrough and naïve infections. Sixteen of 28 confirmed cases of measles in this outbreak were breakthrough infections. A fast provisional classification, based on previous history of measles vaccination and detectable levels of measles IgG in acute serum, correctly identified 14 of the 16 breakthrough infections, confirmed by IgG avidity testing. Measles viral load was significantly lower in nasopharyngeal samples from individuals with breakthrough compared with naïve infections (median Ct-values: 32 and 19, respectively, p < 0.0001). No onward transmission from breakthrough infections was identified. Our results indicate that a high risk of onward transmission is limited to naïve infections. We propose a fast provisional classification of breakthrough measles that can guide contact tracing in outbreak settings.

Herpes simplex encephalitis (HSE) is a common cause of viral encephalitis (HSV-1) characterised by pronounced inflammation and elevated intracranial pressure. We have shown in a rat model that HSV-1 infection causes an interaction between complement factors and proteasomes, leading to formation of proteasome/complement complexes (compleasomes). Exposure of the proteasome regulatory subunit antisecretory factor 1 (AF1) leads to a decrease in intracranial pressure. The aim of this study was to evaluate the acute and prolonged formation of compleasomes in cerebrospinal fluid (CSF) from patients with HSE. Cerebrospinal fluid samples (n = 55) from 24 HSE patients were analysed for compleasome complexes. Samples from healthy controls (n = 23) and patient controls (n = 27) served as baseline information. Sandwich enzyme-linked immunosorbent assay (ELISA) for proteasomes and their complex formation with complement factor 3 or 4, and Western blot for C3 activation were performed on CSF samples. Increased compleasome formation, both presenting as an initial formation and showing exposure of subunit AF1 in the compleasomes, was found in CSF samples drawn from patients with HSE compared with samples from the control groups (p < 0.0005). The total protein CSF concentration was equal in all groups. The levels were higher in the acute phase compared with late in the disease course (p < 0.0005). Complement 3 breakdown product iC3b was detected in CSF samples of the HSE patients. The early increased formation of compleasomes in CSF suggests that this complex may be involved in host defence against HSE.

Background: Herpes simplex encephalitis (HSE) is a devastating disease, often leaving patients with severe disabilities. It has been shown that IgG anti-N-methyl-d-aspartate receptor (NMDAR) antibodies appear in approximately 25% of HSE patients and could be associated with impaired recovery of cognitive performance., Objectives: To characterize the prevalence of IgM and IgA anti-NMDAR antibodies in HSE patients, in relation to subsequent development of IgG anti-NMDAR and correlation to cognitive performance., Study Design: A total of 48 subjects were included from a previously described cohort of patients with HSE verified by HSV-1 PCR. Cerebrospinal fluid (CSF) and serum samples drawn close to onset of disease, after 14-21 days of iv aciclovir treatment and after 90 days of follow-up, were analyzed for the presence of IgM and IgA anti-NMDAR, and related to IgG anti-NMDAR. Antibody levels were correlated to the recovery of cognitive performance, as estimated by the Mattis Dementia Rating Scale (MDRS), for a total of 24 months., Results: In total, 27 of 48 (56%) study subjects were anti-NMDAR positive, defined as the presence of IgG (12/48, 25%), IgM (14/48, 29%) or IgA (13/48, 27%) antibodies in CSF and/or serum. IgM or IgA anti-NMDAR did not predict subsequent IgG autoimmunization and did not correlate to cognitive outcome. IgG anti-NMDAR serostatus, but not antibody titers, correlated to impaired recovery of cognitive performance., Conclusions: A majority of HSE patients develop IgG, IgM or IgA anti-NMDAR antibodies. However, the predictive value and clinical relevance of non-IgG isotypes remains to be shown in this setting., (Copyright © 2018 Elsevier B.V. All rights reserved.)