Viral RNA In Cerebrospinal Fluid Research Articles

Cerebrospinal fluid cytokines in COVID-19: a review and meta-analysis.

Neurological involvement can occur in patients with SARS-CoV-2 infections, resulting in coronavirus disease 2019 (COVID-19). Cytokine alterations are associated with neurological symptoms in COVID-19. We performed a review of cytokines in the cerebrospinal fluid (CSF) of patients with COVID-19. Two reviewers independently searched PubMed for all relevant articles published prior to November 11, 2022. Active SARS-CoV-2 infection and CSF cytokine analyses were required for inclusion. Three-hundred forty-six patients with COVID-19 and 356 controls from 28 studies were included. SARS-CoV-2PCR was positive in the CSF of 0.9% (3/337) of patients with COVID-19. Thirty-seven different cytokines were elevated in the CSF of patients with COVID-19 when compared to controls and the standards set forth by individual assays used in each study. Of the 37 cytokines, IL-6 and IL-8 were most commonly elevated. CSF IL-6 is elevated in 60%, and CSF IL-8 is elevated in 51% of patients with COVID-19. Levels of several inflammatory cytokines are elevated in the CSF of patients with COVID-19, and SARS-CoV-2 PCR is often not isolated in the CSF of patients with COVID-19. Many patients with COVID-19 have neurological symptoms and given the cytokine elevations in the absence of detectable viral RNA in cerebrospinal fluid; further study of the CSF cytokine profiles and pathogenesis of neurological symptoms in COVID-19 is needed.

Neurological Complications in COVID-19 Patients: Can Analysis of Specific Antibodies and Viral RNA in Paired Cerebrospinal Fluid and Serum be Used for Accurate Diagnosis of SARS-CoV-2 Neuroinflammatory Disease? A Case Series

Neurological complications during and after SARS-CoV-2 infection have been frequently described. The detection of either SARS-CoV-2 RNA or specific antibodies against SARS-CoV-2 in cerebrospinal fluid in the context of concomitant neurological manifestations indicates neuroinfection. This is a retrospective descriptive analysis of cerebrospinal fluids and serum samples from 2 hospitalized patients and autopsy findings from 2 patients who died at home. Samples were analysed by 3 independent enzyme-linked immunosorbent assays. Specific antibodies against SARS-CoV-2 were detected in cerebrospinal fluids and paired serum in all 4 cases. Levels of antibodies in cerebrospinal fluids were highest in samples from a deceased man with critical progression of COVID-19 and detectable SARS-CoV-2 viral RNA in cerebrospinal fluid, serum, 4 brain biopsies and 15 additional tissue samples, though immunohistochemical staining for SARS-CoV-2 in brain tissue did not detect the virus. Detection of SARS-CoV-2 antibodies in paired serum and cerebrospinal fluid may support the presence of SARS-CoV-2 neuroinflammatory disease in patients with COVID-19 and neurological manifestations.

Cerebrospinal fluid type I interferon and cytokine profiles in enteroviral meningitis according to the presence or absence of pleocytosis

Enteroviral meningitis is typically diagnosed as the presence of pleocytosis and of viral RNA in cerebrospinal fluid. However, it was recently reported that more than 50% of infants with enteroviral meningitis diagnosed by polymerase chain reaction had no cerebrospinal fluid pleocytosis. This study investigated type I interferon (IFN) and cytokine profiles in the cerebrospinal fluid based on the presence or absence of cerebrospinal fluid pleocytosis in children with enteroviral meningitis. We included 51 enteroviral meningitis patients showing cerebrospinal fluid pleocytosis (pleocytosis group), 31 enteroviral meningitis patients without cerebrospinal fluid pleocytosis (non-pleocytosis group), and 52 controls (control group) and compared cerebrospinal fluid interleukin 6 (IL-6), IL-8, chemokine (C-X-C motif) ligand 10 (CXCL-10), IFN-α, and IFN-β levels. A significant difference was observed in IL-6, IL-8, and CXCL-10 levels across the three groups, with highest values in the pleocytosis patients, followed by those in the non-pleocytosis and control subjects. IFN-α level was higher in the pleocytosis group than in the non-pleocytosis and control groups. Meanwhile, the IFN-β level was higher in the pleocytosis and non-pleocytosis groups than in the control group (34.54 [31.23-38.59] pg/mL vs. 33.21 [31.23-35.21] pg/mL vs. 0.00 [0.00-0.00]pg/mL, respectively; P<0.001). Furthermore, cerebrospinal fluid IFN-β was detected in all patients with enteroviral meningitis, except one (98.8%) regardless of pleocytosis, whereas it was detected in only two (3.8%) control subjects (P<0.001). The cerebrospinal fluid cytokine profiles remarkably differed based on the presence or absence of cerebrospinal fluid pleocytosis. Further investigations are required to determine whether cerebrospinal fluid IFN-β could be used as a surrogate marker of viral meningitis instead of cerebrospinal fluid pleocytosis.

Clinical and laboratory characteristics of neuroinvasive viral zoonoses detected in continental Croatian regions, 2017-2018

Purpose: To analyze clinical and laboratory characteristics of neuroinvasive viral zoonoses detected in Croatia during 2017-2018. Methods & Materials: From April 2017 to June 2018, a total of 120 patients with neuroinvasive disease from continental Croatian regions were tested for the presence of neuroinvasive zoonotic viruses: tick-borne encephalitis virus (TBEV), West Nile virus (WNV), Usutu virus (USUV), Toscana virus (TOSV), Tahyna virus (TAHV) and lymphocytic choriomeningitis virus (LCMV). Cerebrospinal fluid (CSF) and urine samples were tested for the presence of viral RNA using a real-time RT-PCR and/or nested RT-PCR. Serological tests of serum/CSF samples (IgM/IgG antibodies, IgG avidity) were performed using ELISA (TBEV, WNV, USUV), IFA (TOSV, LCMV) and virus neutralization test (WNV). Results: Etiology was confirmed in 28/23.3% patients: TBEV in 20/16.7% and WNV in 8/6.6% patients by detection of IgM and IgG antibodies of low avidity and/or detection of viral RNA in CSF and urine. Majority of patients with TBEV infection were males (15/75.0%). Although infections were detected in all age groups, 15/75.0% patients were less than 60 years of age. The main clinical symptoms were headache (18/90.0%), weakness (18/90.0%), nausea (12/60.0%) and vomiting (8/40.0%). Fever >39 °C was noted in 16/80.0% patients. CSF leukocyte count ranged from 41-3520/mm3 with mononuclear cell predominance in 15/75.0% patients. All but one patient fully recovered. WNV infection was reported in 5/62.5% males and 3/37.5% females. All but one patient (7/87.5%) were older than 60 years. Majority of patients reported underlying diseases: hypertension (3/37.5%) and cerebrovascular disease (3/37.5%). The main clinical symptoms were headache (5/62.5%) and weakness (5/62.5%), while fever >39 °C was noted in 4/50.0% patients. CSF leukocyte count ranged from 56-1096/mm3 with mononuclear cell predominance in 4/50.0% patients. One patient died. USUV, TOSV, TAHV and LCMV infections were not detected during the tested period. Conclusion: TBEV infections were more common in patients less than 60 years of age, while WNV infections were most common in elderly. High fever was noted in 80.0% TBEV cases compared to 50.0% WNV cases. CSF pleocytosis was higher in TBEV infection.

Human rabies in India: an audit from a rabies diagnostic laboratory.

Rabies, an acute progressive encephalomyelitis, continues to be a serious public health problem in India and many other countries in Asia and Africa. The low level of commitment to rabies control is partly attributable to challenges in laboratory diagnosis and lack of adequate surveillance to indicate the disease burden. A laboratory audit of human rabies cases was undertaken to disseminate information on the clinical, demographic, prophylactic and most importantly the laboratory diagnostic aspects of rabies. A retrospective analysis of all clinically suspected human rabies cases, whose samples were received at a rabies diagnostic laboratory in South India in the last 3 years, was performed. Clinical and demographic details of patients were obtained. The clinical samples included cerebrospinal fluid (CSF), serum, saliva and nuchal skin biopsy collected antemortem, and brain tissue obtained post-mortem. Various laboratory tests were performed for diagnosis. Clinical samples from 128 patients with suspected rabies, from 11 states in India, were received for diagnostic confirmation. About 94% of the victims reported dog-bites, more than a third of them were children and most of the victims did not receive adequate post-exposure prophylaxis. Antemortem confirmation of rabies by a combination of laboratory diagnostic assays (detection of viral RNA in CSF, skin and saliva, and neutralising antibodies in CSF) could be achieved in 40.6% cases. Increasing awareness about adequate post-exposure prophylaxis, additional rabies diagnostic facilities, and enhanced human and animal rabies surveillance to indicate the true disease burden are essential to control this fatal disease.

Urinary detection of toscana virus nucleic acids in neuroinvasive infections

BackgroundToscana virus (TOSV) is a sandfly-borne pathogen causing febrile diseases and neuroinvasive infections in humans. Definitive diagnosis of TOSV infections frequently requires the detection of viral RNA in cerebrospinal fluid (CSF) or in circulation, which can be achieved prior to seroconversion. ObjectivesTo evaluate TOSV excretion in urine and impact of urine as a diagnostic specimen. Study designA total of 82 plasma, CSF and urine samples were collected from 24 individuals with a preliminary diagnosis of atypical viral encephalitis, where frequent bacterial fungal and viral causes were ruled out. Phlebovirus and WNV nucleic acids were investigated via real-time and nested polymerase chain reaction (PCR) assays. Commercial immunofluorescence assays were employed for viral IgM detection. Amplicons were characterized via cloning and sequencing. ResultsPhlebovirus PCR yielded positive results in 7 out of 14 samples that comprise 4 plasma and 3 urine specimens from 3 individuals. Amplicons were characterized as TOSV genotype A. Investigation of the follow-up samples suggested that virus shedding in urine coincides or follows viremia. Despite conserved sequences observed in paired or sequential plasma-urine specimens, L693S substitution in the viral polymerase was characterized in a urine sample. ConclusionsThese preliminary findings indicate that urine can be employed as a additional clinical sample for TOSV RNA detection in suspected cases, especially in individuals where specimens for viral diagnostics during the early stages of the infection are not available.

Influenza A 2009 H1N1 encephalitis in adults with viral RNA in cerebrospinal fluid

We present 3 cases of influenza A 2009 H1N1 encephalitis occurring in adults, corroborated by viral genome detection in cerebrospinal fluid (CSF) and evidence of meningeal inflammation on brain histopathology. This paper emphasizes the possibility of viral detection in CSF and stresses the lack of an effective treatment for neurological manifestations of influenza.

Cerebrospinal fluid markers that predict SIV CNS disease

Predictive cerebrospinal fluid markers would provide valuable tools for tracking the development and progression of HIV CNS disease. In this study, expression of IL-6, MCP-1, and viral RNA in cerebrospinal fluid collected from SIV-inoculated macaques during acute, asymptomatic, and terminal stages of infection was quantitated to determine whether one or several of these parameters paralleled the severity of SIV encephalitis. Animals that developed moderate to severe SIV encephalitis had significantly elevated levels of CSF IL-6, MCP-1, and SIV RNA during asymptomatic infection and persisting through terminal disease as compared to animals developing mild or no CNS disease.

Neuropathogenesis of Simian Immunodeficiency Virus in Neonatal Rhesus Macaques

Neonatal human immunodeficiency virus (HIV) infection usually occurs intrapartum or postpartum and results in a higher incidence of neurological dysfunction than is seen in adults. To explore the neuropathogenesis of neonatal HIV infection, we infected neonatal macaques with simian immunodeficiency virus (SIV) and followed the course of infection focusing on early time points. Infected neonates had decreased brain growth and mild histological changes in brain that resembled those seen in pediatric AIDS, including perivascular infiltrates of mononuclear cells, mineralization of vessels in the basal ganglia, and gliosis. The perivascular lesions and gliosis were associated with the presence of occasional infected cells that required in situ hybridization with radiolabeled riboprobes for detection. Using this technique, SIV-infected cells were detected in the brain parenchyma within 7 days of infection. These findings were confirmed by nested PCR for SIVgag DNA in brain and RT-PCR for viral RNA in cerebrospinal fluid. Together, these techniques revealed SIV infection of the CNS in 12 of 13 neonates infected with SIVmac239, 3 of 3 infected with SIVmac251, and 2 of 2 infected with SIVmac239/316. The prevalence of CNS infection was indistinguishable from that of older animals infected with the same dose and stock of virus, but neonates appeared to have fewer infected cells in the CNS and detecting them required more sensitive techniques. This observation was true regardless of inoculum and despite the fact that neonates had equal or greater viral loads in the periphery compared with older animals. These data suggest that maturation-dependent host factors have a major impact on the neuropathogenesis of pediatric AIDS.

HIV infection of the central nervous system is characterized by rapid turnover of viral RNA in cerebrospinal fluid.

To assess the kinetics of viral replication and decay in cerebrospinal fluid (CSF), we studied the short-term effects of highly active antiretroviral therapy (HAART) on CSF HIV-1 RNA concentrations. In 15 HIV-positive patients, HIV RNA concentrations were measured in paired CSF and plasma/serum samples. Samples were obtained prior to and 5 to 24 days after initiation or change of HAART. The short-term effects of interruption of HAART were tested in 2 patients. Viral load was measured by the Roche Amplicor assay. During HAART, in 12 of 15 patients a significant reduction of CSF HIV RNA concentration was observed, ranging from 0.55 to 2.77 log10 (median, 1.37 log10). This was paralleled by a reduction of blood viremia ranging from 0.12 to 3.0 log10 (median, 1.65 log10). The median half-life, as calculated from the slopes of the two time-point measurements, for CSF and blood viral load was 2.66 and 2.36 days, respectively. In 2 patients, CSF viral load remained essentially unchanged despite substantial reduction of plasma viral load. In 1 patient, after interruption of HAART, a rapid increase of HIV RNA in the CSF and blood was seen. No correlation was found between the CSF:blood albumin ratio as a measure of the functional integrity of the blood-CSF barrier and the ratio of CSF:blood RNA concentration, which suggests that no major passive influx of HIV RNA moves from the blood into the CSF compartment. However, a correlation existed between the CSF cell count and the CSF viral load (r = 0.74; p < .003). We conclude that, in most HIV-infected individuals, the decay of viral load in the CSF is similarly rapid as that seen in plasma. The rapid kinetics of virus found in the CSF suggest that it may be produced by rapidly proliferating cells, such as lymphocytes.

Human immunodeficiency virus type 1 is present in the cerebrospinal fluid of a majority of infected individuals.

Cerebrospinal fluid (CSF) specimens from 63 patients with different severities of human immunodeficiency virus (HIV-1) infection, including asymptomatic virus carriers, were examined for the presence of HIV-1 by using polymerase chain reaction (PCR) and virus isolation. Polyadenylated RNA, presumably associated with virus particles, was extracted and reverse transcribed, and the pol region was amplified in a nested PCR. Virus could be detected in 90% of the CSF specimens examined by PCR, and data on isolation of virus from CSF were in agreement with these figures. In fact, when several CSF specimens from the same individual were studied, HIV-1 could be isolated from 80% of the patients. The presence of the viral RNA in CSF was independent of the clinical stage of infection and of neurological symptoms. These results show that the spread of HIV-1 to the brain represents an early event during infection and occurs in the majority of asymptomatic individuals.