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Tick-borne encephalitis (TBE) is a viral infection of the CNS caused by TBE virus. With no specific treatment available, the only protection is a formalin-inactivated whole virus vaccine. Primary immunization with European TBE vaccines, as recommended by the manufacturers, consists of three vaccine doses administered within a 1-y period. Protection from vaccination is believed to be mediated by Abs, yet T cells may also have a protective role. We set out to characterize the human CD4+ T cell response throughout primary TBE immunization. The responses were evaluated before vaccination and 1 mo after each vaccine dose. A heterogeneous magnitude of CD4+ T cell-mediated memory responses was observed in regard to lymphoblast expansion and cytokine production (IFN-γ, IL-2, and TNF), with the highest median magnitude detected after the second dose of vaccine. Stimulation with an overlapping peptide library based on structural TBE virus proteins E and C revealed that CD4+ T cells concomitantly producing IL-2 and TNF dominated the responses from vaccinees after each vaccine dose, whereas a control cohort of TBE patients responded mainly with all three cytokines. CD107a expression was not upregulated upon peptide stimulation in the vaccinees. However, CD154 (CD40L) expression on cytokine-positive memory CD4+ T cells significantly increased after the second vaccine dose. Taken together, TBE vaccination induced CD4+ T cell responses dominated by IL-2 and TNF production together with CD154 upregulation and a lower IFN-&#947: response compared with TBE patients. This response pattern was consistent after all three doses of TBE vaccine. [ABSTRACT FROM AUTHOR]

Background. In suspected acute bacterial meningitis (ABM), cerebral computerized tomography (CT) is recommended before lumbar puncture (LP) if mental impairment. Despite guideline emphasis on early treatment, performing CT prior to LP implies a risk of delayed treatment and unfavorable outcome. Therefore, Swedish guidelines were revised in 2009, deleting impaired mental status as a contraindication for LP without prior CT scan. The aim of the present study was to evaluate the guideline revision. Methods. The Swedish quality registry for community-acquired ABM was analyzed retrospectively. Door-to-antibiotic time and outcome were compared among patients treated 2005-2009 (n = 394) and 2010-2012 (n = 318). The effect of different LP-CT sequences was analyzed during 2008-2012. Results. Adequate treatment was started 1.2 hours earlier, and significantly more patients were treated <2 hours from admission 2010-2012 than 2005-2009. Compared with CT before LP, immediate LP resulted in 1.6 hours earlier treatment, significant increase in door-to-antibiotic times of <1 and <2 hours, and a favorable outcome. In 2010-2012, mortality was lower (6.9% vs 11.7%) and the risk of sequelae at follow-up decreased (38% vs 49%) in comparison with 2005-2009. Treatment delay resulted in a significantly increased risk for fatal outcome, with a relative increase in mortality of 12.6% per hour of delay. Conclusions. The deletion of impaired mental status as contraindication for prompt LP and LP without prior CT scan are associated with significantly earlier treatment and a favorable outcome. A revision of current international guidelines should be considered. [ABSTRACT FROM AUTHOR]

Highlights: [•] Seroprotection was studied two years after vaccination against Japanese encephalitis. [•] After Ixiaro primary series, protection appeared to wane first against GI-genotype. [•] The first Ixiaro booster dose should not be delayed beyond two years. [•] A single Ixiaro dose gives protection to JE-MB primed subjects for at least two years. [ABSTRACT FROM AUTHOR]

Current Japanese encephalitis vaccines are derived from strains of genotype III, yet heterologous genotypes are emerging in endemic areas. Inactivated vaccines given to European travelers were found to elicit protective levels of neutralizing antibodies against heterologous strains of genotypes I–IV. [ABSTRACT FROM PUBLISHER]

AIDS, caused by the retrovirus human immunodeficiency virus (HIV), is the leading cause of death of economically active people (age, 15–59 years) in sub-Saharan Africa. The host genetic variability of immune response to HIV and immune reconstitution following initiation of highly active antiretroviral therapy (HAART) is poorly understood. Here we focused on copy number variation of the β-defensin genes, which have been shown to have anti-HIV activity, and are important chemoattractants for Th17 lymphocytes via the chemokine receptor CCR6. We determined β-defensin gene copy number for 1002 Ethiopian and Tanzanian patients. We show that higher β-defensin copy number variation is associated with increased HIV load prior to HAART (P = .005) and poor immune reconstitution following initiation of HAART (P = .003). We suggest a model where variable amounts of β-defensin expression by mucosal cells, due to gene copy number variation, alters the efficacy of recruitment of Th17 lymphocytes to the site of infection, altering the dynamics of infection. [ABSTRACT FROM PUBLISHER]

The new Japanese encephalitis vaccine (JE-VC, Ixiaro) has replaced mouse brain–derived vaccines (JE-MB) associated with serious safety concerns. A single dose of JE-VC effectively boosted immunity in JE-MB–primed travelers. Current recommendations for booster vaccination should be reevaluated.Background. A significant part of the world population lives in areas with endemic Japanese encephalitis (JE). For travelers from nonendemic countries, Vero cell–derived vaccine (JE-VC; Ixiaro) has replaced traditional mouse brain–derived vaccines (JE-MB) associated with safety concerns. The 2 vaccines are derived from different viral strains: JE-VC from the SA14-14-2 strain and JE-MB from the Nakayama strain. No data exist regarding whether JE-VC can be used to boost immunity after a primary series of JE-MB; therefore, a primary series of JE-VC has been recommended to all travelers regardless of previous vaccination history.Methods. One hundred twenty travelers were divided into 4 groups: Volunteers with no prior JE vaccination received primary immunization with (group 1) JE-MB or (group 2) JE-VC, and those primed with JE-MB received a single booster dose of (group 3) JE-MB or (group 4) JE-VC. Immune responses were tested before and 4–8 weeks after vaccination using plaque reduction neutralization test (PRNT) against both vaccine strains.Results. In vaccine-naive travelers, the vaccination response rate for test strains Nakayama and SA14-14-2 was 100% and 87% after primary vaccination with JE-MB and 87% and 94% after JE-VC, respectively. Antibody levels depended on the target virus, with higher titers against homologous than heterologous PRNT50 target strain (P < .001). In travelers primed with JE-MB, vaccination response rates were 91% and 91%, and 98% and 95% after a booster dose of JE-MB or JE-VC, respectively. Subgroup analysis revealed that a higher proportion of primed (98%/95%) than nonprimed (39%/42%) volunteers responded to a single dose of JE-VC (P < .001).Conclusions. A single dose of JE-VC effectively boosted immunity in JE-MB–primed travelers. Current recommendations should be reevaluated.Clinical Trials Registration. NCT01386827. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis (TBE) and neuroborreliosis (NB) are well-known central nervous system (CNS) infections in children. Childhood tick-borne CNS infections are generally described as mild conditions. However, this view has recently been challenged, and the natural course, including potential sequelae, has been debated. If the diseases present with nonspecific symptoms and signs, some children may elude diagnosis. This study estimates the incidence of symptomatic tick-borne CNS infections in children under medical care and describes the spectrum of manifestations. One hundred twenty-four children with neurologic symptoms attending the Pediatric Emergency Department were included prospectively. Anti-TBE virus and anti- Borrelia serology results were analyzed together with inflammatory parameters in the blood and cerebrospinal fluid. Nearly one fourth of the children with neurologic symptoms were diagnosed with a tick-borne CNS infection (TBE, n = 10 [8%] and NB, n = 21 [16.8%]). In general, these children displayed an indistinct medical history and presented with nonspecific signs such as malaise/fatigue and headache. Diagnosis was based on analysis of acute and convalescent sera. Blood inflammatory parameters were nonspecific and did not contribute to the diagnostics. Conclusion: Pediatric tick-borne CNS infections are unexpectedly common and should be considered in children with unspecific and unexplained acute CNS-related symptoms. [ABSTRACT FROM AUTHOR]

Objectives We investigated the long-term effect of efavirenz autoinduction on its plasma/peripheral blood mononuclear cell (PBMC) exposure and the CD4 count, and the importance of sex and pharmacogenetic variations. Methods Treatment-naive HIV patients (n = 163) received efavirenz-based antiretroviral therapy. Plasma and intracellular (PBMC) concentrations of efavirenz and 8-hydroxyefavirenz were determined at weeks 4 and 16 of antiretroviral therapy. CD4 count was determined at baseline, and at weeks 12, 24 and 48. Genotyping for CYP2B6*6, CYP3A5*3, CYP3A5*6, CYP3A5*7, ABCB1 3435C/T and UGT2B7 (−327G→A, *2) was done. Results There was a significant increase in the median plasma (32%) and intracellular (53%) 8-hydroxyefavirenz concentrations with a decrease in the efavirenz metabolic ratio (MR) (calculated by dividing the concentration of efavirenz by that of 8-hydroxyefavirenz) (20% and 5%, respectively) by week 16 compared with at week 4. While the CYP2B6 genotype significantly influenced efavirenz pharmacokinetics at weeks 4 and 16, the effect of the UGT2B7 genotype and sex was significant only at week 16. The Wilcoxon matched pairs test indicated that the change in 8-hydroxyefavirenz concentration and efavirenz MR over time was significant in females and in CYP2B6*1 and UGT2B7*1 carriers. The intracellular 8-hydroxyefavirenz level at week 16 was a negative predictor of the CD4 count at week 24 (P = 0.03) and at week 48 (P = 0.007). CYP2B6 (P = 0.02) and UGT2B7 (P = 0.05) genotypes predicted the CD4 count at week 48. Among CYP2B6*1/*1 and UGT2B7*1/*1 carriers there was no significant change in the mean CD4 count after week 24, while it continuously increased until week 48 in CYP2B6*6 and UGT2B7*2 carriers. Conclusions The effects of long-term efavirenz autoinduction on its plasma/PBMC exposure and the CD4 count over time display wide interpatient variability, partly due to sex and CYP2B6 and UGT2B7 genetic variation. Patients with the CYP2B6*1/*1 and UGT2B7*1/*1 genotypes are at risk of suboptimal immune recovery due to pronounced long-term autoinduction. [ABSTRACT FROM PUBLISHER]

Background: Tick-borne encephalitis virus (TBEV) infections may be asymptomatic or cause severe symptoms in the central nervous system. A mutation in the chemokine receptor 5 gene has been associated with increased risk of TBE but explains only a limited number of cases. Investigations of further risk factors are needed.Method: To investigate the importance of the innate immune response, we analyzed 128 TBE patients, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls, for 3 mutations: 2 in the Toll-like receptor 3 (TLR3) gene and 1 in the 2'-5'-oligoadenylate synthetase (OAS1) gene.Results: Although no association was found between the mutation in the OAS1 gene and TBE, the genotype distribution ofrs3775291, a mutation in TLR3, differed significantly between TBE patients and controls; 61%, 32%, and 7% of the TBE patients were carriers of the wild-type, heterozygous, and mutant genotype of rs3775291, respectively. The corresponding percentages among healthy controls (n = 126) were 52%, 29%, and 19% (P = .02), and among AME patients (n = 75) were 47%, 32%, and 21% (P = .009). Additionally, the wild-type rs3775291 allele was more common among TBE patients than among healthy controls (allele frequency, .768 vs .663; P = .01).Conclusion: A functional TLR3 is a risk factor for TBEV infection. [ABSTRACT FROM AUTHOR]

Abstract: Tick-borne encephalitis (TBE) is a major disease of the central nervous system in Europe and is endemic in Sweden with about 200 notified cases annually. The far most effective protective measure against TBE is active immunisation. The vaccines available today induce a high degree of protection in field studies. However, vaccine failures have occasionally been reported and may be overlooked due to different, and sometimes confusing, antibody kinetics in vaccinees with TBEV infection. In this study, 27 patients with clinical and serological evidences of TBE despite adequate immunisation are presented. Vaccination failure is characterized by a slow, and initially non-detectable, development of the specific TBEV-IgM response, seen together with a rapid rise of IgG and neutralising antibodies in serum. The majority (70%) of the patients were more than 50 years of age, which may implicate a need for a modified immunisation strategy in the elderly. [Copyright &y& Elsevier]

Tickborne encephalitis (TBE) virus infections can be asymptomatic or cause moderate to severe injuries of the central nervous system. Why some individuals develop severe disease is unknown, but a role for host genetic factors has been suggested. To investigate whether chemokine receptor CCR5 is associated with TBE, CCR5Δ32 genotyping was performed among Lithuanian patients with TBE (n = 129) or with aseptic meningoencephalitis (n = 76) as well as among control subjects (n = 134). We found individuals homozygous for CCR5Δ32 (P = .026) only among patients with TBE and a higher allele prevalence among patients with TBE compared with the other groups studied. CCR5Δ32 allele prevalence also increased with the clinical severity of disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Smear-negative tuberculosis occurs more frequently in human immunodeficiency virus (HIV)-infected patients than in non-HIV-infected patients. Besides, there are substantial numbers of patients who cannot produce sputum, making the diagnosis of pulmonary tuberculosis (PTB) difficult. AIMS: To evaluate the relative yield of pre- and post-bronchoscopy sputum and bronchoalveolar lavage (BAL) in 'sputum smear'-negative, HIV-positive patients. SETTINGS: A tertiary care referral hospital in Addis Ababa. MATERIALS AND METHODS: Acid-fast stain (AFS) using the concentration technique was done on 85 pre-bronchoscopy sputum and 120 BAL samples. Direct AFS was done on all BAL and 117 post-bronchoscopy sputum samples. Culture for Mycobacterium tuberculosis (MTB) was done for all sputa and BAL. RESULTS: MTB was isolated from 26 (21.7%), 23 (19.7%) and 13 (15.3%) of BAL, post- and pre-bronchoscopy sputum cultures respectively. AFS on pre-bronchoscopy sputum using concentration technique and direct AFS on BAL together detected 11 (41%) of the 27 culture-positive cases. In patients who could produce sputum, the sensitivity of pre-bronchoscopy sputum culture (13/85, 15.3%) was comparable to BAL (12/85, 14%) and post-bronchoscopy sputum (12/85, 14%). In patients who could not produce sputum, however, both BAL (12/35, 40%) and post-bronchoscopy sputum (12/32, 31.4%) detected significantly more patients than those who could produce sputum (P=0.002, P=0.028 respectively). CONCLUSION: In HIV-infected patients, AFS by concentration method on pre-bronchoscopy sputum and direct AFS on BAL in patients who cannot produce sputum are the preferred methods of making a rapid diagnosis. BAL culture seems to add little value in patients who can produce sputum; therefore, bronchoscopy should be deferred under such circumstances. [ABSTRACT FROM AUTHOR]

Abstract: The antibody response to vaccination against tick-borne encephalitis (TBE) with FSME-Immun™ Inject (Immuno AG/Baxter) was studied in 535 persons, mainly adults, attending a vaccination centre in Stockholm, Sweden. Emphasis was laid on long-term follow-up. Antibody activity was measured by three different serological test systems: a commercial ELISA kit, a hemagglutination inhibition (HI) test and a neutralization test (RFFIT). The neutralization test proved to be the most sensitive assay for the detection of the vaccine response, which was demonstrable in the majority of vaccinees (>90% after three and >98% after four and five vaccinations, respectively). ELISA and HI were less sensitive for antibody measurement during primary immunization. Neutralizing antibody activity persisted prior to the third dose in 77% of the vaccinees and prior to the fourth to sixth doses in 89–95% of the vaccinees. ELISA activity, but no neutralizing activity, was found in some individuals. Based on our data and previous experience of vaccine failures after two doses, a more condensed three-dose vaccination schedule may be advantageous and ought to be tested. The persistence of neutralizing antibodies justifies further studies of the antibody responses after the fourth dose for periods beyond the recommended 3-year booster intervals. [Copyright &y& Elsevier]

Of 250 consecutively admitted patients with central nervous system (CNS) infections who were treated during a 1-year period, all 133 patients with tickborne encephalitis (TBE) were included in a prospective follow-up study. TBE presented as mild (meningeal) in 43.6% of patients and as moderate or severe (encephalitic) in 43.6% and 12.8% of patients, respectively. Paralytic disease was observed in 3.8% of the subjects, and cranial nerve injury was observed in 5.3%. One patient died of TBE. Permanent CNS dysfunction after 1 year was found in 30.8% of patients; in 8.5% of all TBE cases, severe disabilities required adjustment of daily activities. Corticosteroid treatment did not seem to improve outcome. A progressive course of TBE was noted in 2 patients. The risk of incomplete recovery was significantly higher among patients with the encephalitic form of TBE (odds ratio, 4.066; 95% confidence interval, 1.848-8.947). In conclusion, TBE is an important pathogen in CNS infection in the Kaunas region of Lithuania, and it causes long-lasting morbidity in one-third of cases. [ABSTRACT FROM AUTHOR]

In this article the author discusses vaccination of children . He says that the benefits of vaccination are certain and critical evaluation of childhood vaccinations is warranted. He also says that the effectiveness of a vaccine when used in a general vaccination programme is generally analysed by observing the target disease incidence before and after introduction of the intervention.

Background: The incidence of Tick-borne encephalitis (TBE) has increased during the last decades in Europe. Our aim was to assess the clinical characteristics and outcome of TBE patients in Region Stockholm, as a high-risk area in Sweden., Methods: The notification database at the regional Department of Communicable Disease Control and Prevention was used to identify TBE cases during 2006-2015. Clinical data was retrieved from the included patients' medical records. The associations of specific variables to predefined outcomes of disease severity were evaluated with multivariate logistic regression models., Results: Of 1004 identified TBE cases, 703 adult patients were included. Sixty-one percent were men, and the median age was 50 years (range 18-94). The majority were non-vaccinated. Comorbidity was present in 34%, and 4% had immunomodulatory therapy. Seventy-five percent were hospitalised, and 11% had severe disease. More than 70% of the 79 patients followed up for more than 6 months had persisting symptoms. The case fatality rate was 1.4%, with 15% in the group with immunomodulatory treatment. In the multivariate analysis, severe disease was associated with underlying comorbidities, age ≥50 years, and previous complete TBE vaccination., Conclusion: This is the largest cohort of TBE patients in Scandinavia. Our findings of a more severe course of disease in patients of older age, with immunomodulatory therapy, with comorbidities, and vaccination breakthrough infections must be interpreted in the context of hospitalised patients. Optimised prevention is needed for patients with immunomodulatory therapy, given the considerable case fatality rate. Follow-up visits and rehabilitation should be better standardised., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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 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.)

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Parkinson's disease (PD) is a neurodegenerative disease linked with the loss of dopaminergic neurons in the brain region called substantia nigra and caused by unknown pathogenic mechanisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogenesis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson's disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic properties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson's disease cases and in only 1 out of 11 controls ( p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer's disease. Potentially successful antiviral treatment in Alzheimer's disease suggests a similar treatment for Parkinson's disease. Amantadine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

Background: Accumulating data suggest infectious agents are involved in Alzheimer's disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression., Objective: The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression., Methods: Sixty-nine patients 60-85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed., Results: The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met ( p  = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-β in Apovir at 9 months ( p  = 0.0330) but no change in placebo., Conclusion: This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process., Competing Interests: Nina Lindblom and Jacob Westman are full time employees at Apodemus AB. Roger Bullock and Mikael Åström and Suzanne Hendrix are consultants at Apodemus. Lars-Olof Wahlund and Lars Lindquist have not been personally compensated for their work on the clinical trial., (© 2021 – The authors. Published by IOS Press.)

Tick-borne encephalitis (TBE) is a viral infection of the CNS caused by TBE virus. With no specific treatment available, the only protection is a formalin-inactivated whole virus vaccine. Primary immunization with European TBE vaccines, as recommended by the manufacturers, consists of three vaccine doses administered within a 1-y period. Protection from vaccination is believed to be mediated by Abs, yet T cells may also have a protective role. We set out to characterize the human CD4 + T cell response throughout primary TBE immunization. The responses were evaluated before vaccination and 1 mo after each vaccine dose. A heterogeneous magnitude of CD4 + T cell-mediated memory responses was observed in regard to lymphoblast expansion and cytokine production (IFN-γ, IL-2, and TNF), with the highest median magnitude detected after the second dose of vaccine. Stimulation with an overlapping peptide library based on structural TBE virus proteins E and C revealed that CD4 + T cells concomitantly producing IL-2 and TNF dominated the responses from vaccinees after each vaccine dose, whereas a control cohort of TBE patients responded mainly with all three cytokines. CD107a expression was not upregulated upon peptide stimulation in the vaccinees. However, CD154 (CD40L) expression on cytokine-positive memory CD4 + T cells significantly increased after the second vaccine dose. Taken together, TBE vaccination induced CD4 + T cell responses dominated by IL-2 and TNF production together with CD154 upregulation and a lower IFN-γ response compared with TBE patients. This response pattern was consistent after all three doses of TBE vaccine., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Tick-borne encephalitis virus (TBEV) is a leading cause of viral meningoencephalitis in many parts of Europe and eastwards in Asia, with high morbidity and often long-term neurologic sequelae. With no treatment available, studies of the immune response to TBEV are essential for the understanding of the immunopathogenesis of tick-borne encephalitis and for the development of therapeutics. We have previously demonstrated that CD8 + T cell responses in peripheral blood in patients with acute TBEV peak at around 7 d after hospitalization in the neuroinvasive phase of the disease. In this study, we identified six novel TBEV HLA-A2- and HLA-B7-restricted epitopes, all derived from the nonstructural proteins of TBEV. This identification allowed for a comprehensive phenotypic and temporal analysis of the HLA-A2- and HLA-B7-restricted Ag-specific CD8 + T cell response during the acute stages of human TBEV infection. HLA-A2- and HLA-B7-restricted TBEV epitope-specific effector cells predominantly displayed a CD45RA - CCR7 - CD27 + CD57 - phenotype at day 7, which transitioned into separate distinct phenotypes for HLA-A2- and HLA-B7-restricted TBEV-specific CD8 + T cells, respectively. At day 21, the most prevalent phenotype in the HLA-A2-restricted CD8 + T cell populations was CD45RA - CCR7 - CD27 + CD57 + , whereas the HLA-B7-restricted CD8 + T cell population was predominantly CD45RA + CCR7 - CD27 + CD57 + Almost all TBEV epitope-specific CD8 + T cells expressed α4 and β1 integrins at days 7 and 21, whereas the bulk CD8 + T cells expressed lower integrin levels. Taken together, human TBEV infection elicits broad responses to multiple epitopes, predominantly derived from the nonstructural part of the virus, establishing distinct maturation patterns for HLA-A2- and HLA-B7-restricted TBEV epitope-specific CD8 + T cells., (Copyright © 2018 The Authors.)

Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanisms may contribute to varying extents to neurological damage. Although the brain damage is believed to depend, to a varying degree, on the intrathecal host immune response, the use of corticosteroids in viral CNS infections is scarcely studied, as is specific treatment for neuroinflammation. Improved antiviral and immunomodulating treatment is desirable. Since neurological sequelae are still abundant, follow-up after severe viral CNS disease must include a neuropsychological assessment and an individually adapted rehabilitation plan.

Background: Pulmonary tuberculosis (TB), bacterial pneumonia (BP) and Pneumocystis pneumonia (PCP), account for the major causes of pneumonia-like syndromes seen in HIV-AIDS patients and have overlapping clinical and chest x-ray findings pausing challenge to early diagnosis and treatment in Africa. The accuracy of chest x-ray (CXR) interpretations, inter-observer agreement, degree of chest x-ray overlapping, and distinguishing features among these common lung infections was assessed at Tĩkur Anbessa hospital, a tertiary care referral hospital in Addis Ababa, Ethiopia., Patients and Methods: chest x-rays were independently assessed by two radiologists blinded to the clinical between March 2004 and July 2005, the radiographic presentation of 131 smear-negative, HIV-positive patients with atypical laboratory data., Results: One hundred and twenty-four definite diagnoses were made in 107 (82%) of the 131 patients and PCP, BP and pulmonary TB combined accounted for 92% of the diagnoses. The chest x-ray interpretation had high sensitivity (88%), negative predictive value (NPV) (90%), and inter-observer agreement (84%) for PCP Thirty-six percent of the infections mimicked one another, of which BP accounted for the major share. BP mimicked PCP and pulmonary TB in 39% and 20% respectively. Diffuse and bilateral alveolar infiltrates (DBAI) and acinar CXR features discriminated between PCP, pulmonary TB and BP (P < 0.05) while Diffuse bilateral fine interstitial infiltrates (DBFI) did not (p > 0.05). The level of agreement between the radiologists was 79%. There was no exclusively distinguishing radiographic feature amongst the three diseases., Conclusions: Overlapping clinical and radiographic features often occurs as is co-existing infections in HIV-AIDS patients with respiratory symptoms. Therefore, definitive microbiological method should be the main tool to expedite early diagnosis and treatment in HIV-infected patients with respiratory symptoms.

We review the epidemiological and clinical characteristics of tick-borne encephalitis, and summarise biological and virological aspects that are important for understanding the life-cycle and transmission of the virus. Tick-borne encephalitis virus is a flavivirus that is transmitted by Ixodes spp ticks in a vast area from western Europe to the eastern coast of Japan. Tick-borne encephalitis causes acute meningoencephalitis with or without myelitis. Morbidity is age dependent, and is highest in adults of whom half develop encephalitis. A third of patients have longlasting sequelae, frequently with cognitive dysfunction and substantial impairment in quality of life. The disease arises in patchy endemic foci in Europe, with climatic and ecological conditions suitable for circulation of the virus. Climate change and leisure habits expose more people to tick-bites and have contributed to the increase in number of cases despite availability of effective vaccines. The serological diagnosis is usually straightforward. No specific treatment for the disease exists, and immunisation is the main preventive measure.

Objective: To investigate the prevalence of Pneumocystis carinii in consecutive HIV-positive patients with suspected pulmonary tuberculosis (PTB) attending a university hospital in Ethiopia., Methods: A PCR for P. carinii and an indirect immunoflorescence (IF) assay were performed on expectorated sputum samples from: 119 HIV-1-positive patients with negative smears and sputum cultures for Mycobacterium tuberculosis; 96 HIV-1-positive patients with culture-verified PTB; and 97 HIV-negative patients with negative mycobacterial cultures and 72 HIV-negative patients with culture-verified PTB, serving as controls. Outcome of PCR and IF were compared with the chest radiographic (CXR) and initial clinical diagnosis., Results: In the HIV+PTB- group, P. carinii was found in 10.9% by IF, 8.4% by single PCR (sPCR) and 30.3% by nested PCR (nPCR). In the HIV+PTB+ group, 3.1% were P. carinii positive by IF and sPCR and 13.5% by nPCR. All IF- and sPCR-positive samples were nPCR positive. In the HIV-PTB+ and HIV-PTB- groups, 4.2% and 3.1% were nPCR positive, respectively. Six out of eight HIV+PTB- patients with CXR suggesting P. carinii pneumonia (PCP) were IF and/or nPCR positive for P. carinii. In the IF-positive and nested PCR-positive HIV+PTB- patients more than one-third were interpreted as PTB by CXR whereas only one patient was diagnosed with clinical PCP., Conclusions: P. carinii is prevalent in HIV-positive PTB suspects, suggesting that PCP may be an important, but not well recognized, differential diagnosis. Our findings have implications for treatment and primary prophylaxis for PCP in Ethiopia.

Inflammatory recruitment of leukocytes into the cerebrospinal fluid (CSF) during bacterial meningitis has been shown to contribute to the neurological damage commonly associated with this disease. In this study we tested whether inhibition of firm leukocyte adhesion to vascular endothelium could reduce leukocyte recruitment into the subarachnoid space (SAS) and into the skin in rabbits challenged with pneumococcal cell wall (PCW) antigen. PCW was given either as an intracisternal or an intradermal (i.d.) injection. Intravenous (i.v.) treatment with a monoclonal antibody (mAb), IB4, against the leukocytic adhesion molecule CD18 has previously been documented to attenuate leukocyte CSF accumulation in experimental bacterial meningitis. In the present study, i.v. treatment with anti-CD18 mAbs (IB4) only tended to inhibit CSF leukocyte influx in animals with PCW-induced meningitis. However, if the antigen was injected i.d., treatment i.v. with the same mAb (IB4) dramatically reduced leukocyte accumulation in the skin. Our findings indicate that the mechanisms responsible for PCW-induced inflammatory accumulation of leukocytes in skin and meninges are different.