Clinical course and peculiarities of Parechovirus and Enterovirus central nervous system infections in newborns: a single-center experience.

Parechovirus (HpEV) and Enterovirus (EV) infections in children mostly have a mild course but are particularly fearsome in newborns in whom they may cause aseptic meningitis, encephalitis, and myocarditis. Our study aimed to describe the clinical presentations and peculiarities of CNS infection by HpEV and EV in neonates. This is a single-center retrospective study at Istituto Gaslini, Genoa, Italy. Infants aged ≤ 30 days with a CSF RTq-PCR positive for EV or HpEV from January 1, 2022, to December 1, 2023, were enrolled. Each patient's record included demographic data, blood and CSF tests, brain MRI, therapies, length of stay, ICU admission, complications, and mortality. The two groups were compared to identify any differences and similarities. Twenty-five patients (15 EV and 10 HpEV) with a median age of 15 days were included. EV patients had a more frequent history of prematurity/neonatal respiratory distress syndrome (p = 0.021), more respiratory symptoms on admission (p = 0.012), and higher C-reactive protein (CRP) levels (p = 0.027), whereas ferritin values were significantly increased in HpEV patients (p = 0.001). Eight patients had a pathological brain MRI, equally distributed between the two groups. Three EV patients developed myocarditis and one HpEV necrotizing enterocolitis with HLH-like. No deaths occurred.  Conclusion: EV and HpEV CNS infections are not easily distinguishable by clinical features. In both cases, brain MRI abnormalities are not uncommon, and a severe course of the disease is possible. Hyper-ferritinemia may represent an additional diagnostic clue for HpEV infection, and its monitoring is recommended to intercept HLH early and initiate immunomodulatory treatment. Larger studies are needed to confirm our findings. What is Known: • Parechovirus and Enteroviruses are the most common viral pathogens responsible for sepsis and meningoencephalitis in neonates and young infants. • The clinical course and distinguishing features of Parechovirus and Enterovirus central nervous system infections are not well described. What is New: • Severe disease course, brain MRI abnormalities, and complications are not uncommon in newborns with Parechovirus and Enteroviruses central nervous system infections. • Hyper-ferritinemia may represent an additional diagnostic clue for Parechovirus infection and its monitoring is recommended.

Lipid droplets in Zika neuroinfection: Potential targets for intervention?

Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence in various cell types in the brain and for their suggested involvement in neurodevelopment and neurodegenerative diseases. Only recently have the roles of LD in neuroinfections begun to be explored. Recent findings reveal that lipid remodelling and increased LD biogenesis play important roles for Zika virus (ZIKV) replication and pathogenesis in neural cells. Moreover, blocking LD formation by targeting DGAT-1 in vivo inhibited virus replication and inflammation in the brain. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development. Here, we review the progress in understanding LD functions in the central nervous system in the context of the host response to Zika infection.

An In Vivo Model of Echovirus-Induced Meningitis Defines the Differential Roles of Type I and Type III Interferon Signaling in Central Nervous System Infection.

Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation are poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We show that expression of the human homologue of the primary echovirus receptor, the neonatal Fc receptor (FcRn), is not sufficient for infection of the brains of neonatal mice. However, ablation of type I, but not III, interferon (IFN) signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms, including delayed motor skills and hind-limb weakness. Using this model, we defined the immunological response of the brain to echovirus infection and identified key cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6), that were induced by this infection. Lastly, we showed that echoviruses specifically replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections that delineates the differential roles of type I and type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral infections within the meninges. IMPORTANCE Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the FcRn, the primary receptor for echoviruses, and ablation of type I IFN signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.

Detection and genome characterization of Middelburg virus strains isolated from CSF and whole blood samples of humans with neurological manifestations in South Africa.

BACKGROUND: The Old world Alphavirus, Middelburg virus (MIDV), is not well known and although a few cases associated with animal illness have previously been described from Southern Africa, there has been no investigation into the association of the virus with human illness. The current study aimed to investigate possible association of MIDV infection with febrile or neurological manifestations in hospitalized or symptomatic patients fromGauteng, South Africa. METHODS: This study is a descriptive retrospective and prospective laboratory based study. Archived cerebrospinal fluid (CSF) samples submitted to the National Health Laboratory Service (NHLS), Tshwane Academic division for viral investigation from public sector hospitals in Gauteng as well as EDTA (ethylenediaminetetraacetic acid) whole blood samples from ad hoc cases of veterinary students, presenting with neurological and febrile illness, were selected and screened for the presence of alphaviruses using real-time reverse transcription(rtRT) PCR.Virus isolations from rtRT-PCR positive samples were conducted in Vero cell culture and used to obtain full genome sequences. Basic descriptive statistical analysis was conducted using EpiInfo. RESULTS: MIDV was detected by rtRT-PCR in 3/187 retrospective CSF specimens obtained from the NHLS from hospitalised patients in the Tshwane region of Gauteng and 1/2 EDTA samples submitted in the same year (2017) from ad hoc query arbovirus cases from veterinary students from the Faculty of Veterinary Science University of Pretoria.Full genome sequences were obtained for virus isolates from two cases; one from an EDTA whole blood sample (ad hoc case) and another from a CSF sample (NHLS sample).Two of the four Middelburg virus positive cases,for which clinical information was available, had other comorbidities or infections at the time of infection. CONCLUSION: Detection of MIDV in CSF of patients with neurological manifestations suggests that the virus should be investigated as a human pathogen with the potential of causing or contributing to neurological signs in children and adults.

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection.

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. ANN NEUROL 2022;91:150-157.

Cellular and Molecular Effects of SARS-CoV-2 Linking Lung Infection to the Brain.

In December 2019, a new viral disease emerged and quickly spread all around the world. In March 2020, the COVID-19 outbreak was classified as a global pandemic and by June 2021, the number of infected people grew to over 170 million. Along with the patients' mild-to-severe respiratory symptoms, reports on probable central nervous system (CNS) effects appeared shortly, raising concerns about the possible long-term detrimental effects on human cognition. It remains unresolved whether the neurological symptoms are caused directly by the SARS-CoV-2 infiltration in the brain, indirectly by secondary immune effects of a cytokine storm and antibody overproduction, or as a consequence of systemic hypoxia-mediated microglia activation. In severe COVID-19 cases with impaired lung capacity, hypoxia is an anticipated subsidiary event that can cause progressive and irreversible damage to neurons. To resolve this problem, intensive research is currently ongoing, which seeks to evaluate the SARS-CoV-2 virus' neuroinvasive potential and the examination of the antibody and autoantibody generation upon infection, as well as the effects of prolonged systemic hypoxia on the CNS. In this review, we summarize the current research on the possible interplay of the SARS-CoV-2 effects on the lung, especially on alveolar macrophages and direct and indirect effects on the brain, with special emphasis on microglia, as a possible culprit of neurological manifestation during COVID-19.

Risk factors for neurological complications in children with Flavivirus infection.

This study aims to characterize the acute neurological manifestations caused by DENV, ZIKV, and YFV during hospitalization; identify the risk factors associated with persistent neurological complications after discharge; and evaluate the time to resolution during clinical follow-up. A prospective study evaluated 505 children, between March 2014 and July 2019, hospitalized with neurological manifestations and that doctors suspected infection of the central nervous system (CNS). Viral infection of collected cerebrospinal fluid (CSF) was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). Patients were clinically followed up after hospital discharge. Analysis of predictive factors and survival curves was performed. This study identified clinical symptoms and changes in the CSF laboratory, electroencephalogram (EEG), and CNS image as predictors of complications in children with confirmed infection in the CNS by DENV, ZIKV, or YFV. No statistical difference was found (p value 0.574) in the time to the resolution of complications in children after hospital discharge between the three types of flaviviruses. Children with YFV, detected in CSF samples, had a 53% higher risk of developing neurological complications. Performing etiological diagnosis by RT-PCR of CSF samples of children with neurological manifestations, especially during Flavivirus outbreaks, is an essential tool for improving the prognosis and clinical follow-up of these patients.

Viral and Prion Infections Associated with Central Nervous System Syndromes in Brazil.

Virus-induced infections of the central nervous system (CNS) are among the most serious problems in public health and can be associated with high rates of morbidity and mortality, mainly in low- and middle-income countries, where these manifestations have been neglected. Typically, herpes simplex virus 1 and 2, varicella-zoster, and enterovirus are responsible for a high number of cases in immunocompetent hosts, whereas other herpesviruses (for example, cytomegalovirus) are the most common in immunocompromised individuals. Arboviruses have also been associated with outbreaks with a high burden of neurological disorders, such as the Zika virus epidemic in Brazil. There is a current lack of understanding in Brazil about the most common viruses involved in CNS infections. In this review, we briefly summarize the most recent studies and findings associated with the CNS, in addition to epidemiological data that provide extensive information on the circulation and diversity of the most common neuro-invasive viruses in Brazil. We also highlight important aspects of the prion-associated diseases. This review provides readers with better knowledge of virus-associated CNS infections. A deeper understanding of these infections will support the improvement of the current surveillance strategies to allow the timely monitoring of the emergence/re-emergence of neurotropic viruses.

The spectrum of Epstein-Barr virus infections of the central nervous system after organ transplantation.

BACKGROUND: Epstein-Barr virus (EBV)-related neurologic complications have a diverse presentation in transplant recipients, creating diagnostic and therapeutic challenges for clinicians. In this case series, we report unique manifestations of EBV related neurologic complications following solid organ transplant and highlight pitfalls in management. CASE PRESENTATIONS: A retrospective search of the electronic medical record of all patients from January 2015 to December 2020 who underwent solid organ transplantation and had central nervous system complications as determined by ICD-10 codes were included. Three patients with unique manifestation of EBV-related neurologic complications after liver transplantation were identified. The first was a 52-year-old man with a live-donor liver transplant 11 years prior for Budd-Chiari syndrome presented with several weeks of headache and several lesions on brain MRI; he was diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. The second patient was a 63-year-old man with a deceased-donor liver transplant 16 years prior for alpha-1-antitrypsin deficiency and was found to have a stroke; he was diagnosed with EBV encephalitis. The final patient was a 75-year-old woman with a deceased-donor liver transplant six years prior for primary biliary cirrhosis who presented with four months of gait instability; she was diagnosed with EBV myelitis. A review of the literature was performed to supplement description of the different diseases. CONCLUSIONS: EBV-related central nervous infection in post-transplant patients can manifest in a variety of neurologic syndromes, which can be challenging to diagnose. Careful correlation of clinical, pathologic, and radiologic findings and a high index of suspicion are crucial in identification and appropriate management.

Parent-administered Neurodevelopmental Follow up in Children After Picornavirus CNS Infections.

BACKGROUND: Data on the neurodevelopment of children who experienced central nervous system (CNS) infections with enteroviruses (EV) or parechoviruses (hPeV) is scarce and mostly limited to follow up of short-term outcomes. METHODS: Parents of children who presented between 2014 and 2019, underwent a lumbar puncture and whose cerebrospinal fluid was polymerase chain reaction positive for EV or hPeV, were asked to complete a care-giver-administered neurodevelopmental assessment tool (The Ages and Stages Instrument [ASQ3]). Clinical data of the infective episode were collected from patient notes. RESULTS: Of 101 children, 43 (10 hPeV+, 33 EV+) submitted ASQ3 results. Median age at assessment was 38.9 months (interquartile range, 15.4-54.8), the follow-up interval 3 years (median 37 months; interquartile range, 13.9-53.1). Age, inflammatory markers, and cerebrospinal fluid pleocytosis during the infective event were not associated with ASQ3 scores. In 23 children (17 EV+, 6 hPeV+), no neurodevelopmental concerns were reported. Two more had preexisting developmental delay and were excluded. Of the remaining, 18/41 (43.9%) reported ASQ3 scores indicating need for monitoring or professional review in at least 1 category, not differing by pathogen (EV 14/31, 45.2%; hPeV 4/10, 40%; P = 0.71). Seven children will require formal review, scoring ≥2 SD below the mean in at least 1 category (6/31 EV+, 1/10 hPeV+, P = 0.7), 3 scored ≥2 SD below the mean in more than 1 area. CONCLUSIONS: Parent-administered developmental assessment of children with a history of early picornavirus infection of the CNS identified a subgroup that requires formal neurodevelopmental review. Wider application of community-based developmental screening will complement our understanding of the impact of CNS infections in early childhood.

Constitutive and latent immune mechanisms exert 'silent' control of virus infections in the central nervous system.

Viral infections in the central nervous system (CNS) can lead to severe disease manifestations often mediated by a combination of viral cytopathic effects and immunopathology. Moreover, neuronal tissue and brain activities are highly sensitive to excessive inflammation that disturb homeostasis. Immune responses to virus infections in the CNS should therefore be tightly balanced and limited in magnitude and duration to avoid immunopathology and tissue damage. Recent data from genetic studies of patients with viral infections in the CNS as well as experimental cell and animal models have provided evidence of non-redundant roles for constitutive and latent immune mechanisms, which mediate a first line of antiviral control without significantly triggering inflammatory activities. Collectively, accumulating data suggest the existence of a layer of immune mechanisms in the CNS exerting immediate control of infection, hence buffering the need for activation of more potent immune reactions with inherent potential to induce immunopathology and disease.

Impact of the FilmArray meningitis/encephalitis panel on antimicrobial duration among patients with suspected central nervous system infection.

Ten controlled studies evaluated antimicrobial use following implementation of the FilmArray meningitis and encephalitis panel versus usual care. Only one-half of studies identified significant reductions in antibiotic duration, with 8/10 reporting modest reductions for acyclovir. Coupling the FilmArray meningitis and encephalitis panel with interventions by antimicrobial stewardship programs may help enhance its clinical impact.

Arboviral central nervous system infections.

PURPOSE OF REVIEW: This review provides an overview of arthropod-borne virus (arbovirus) infections that are important causes of human neurological infections world-wide. As many of the individual viruses in a specific genus or family cause overlapping clinical syndromes, this review discusses important viruses in groups to highlight some of the similarities and differences in groups of neuroinvasive arbovirus infections. RECENT FINDINGS: Arboviruses that cause neurological infections in humans continue to emerge and distribute to new regions. The geographic range of the vectors, the hosts and subsequent arbovirus infections in humans continues to expand and evolve. As emerging arboviruses move into new geographic regions, it is important to examine the associated epidemiological and clinical impacts of these infections as they enter new populations. SUMMARY: Arboviruses from the Flaviviridae, Togaviridae and Bunyaviridae families continue to emerge and spread into new regions. The arboviruses within these virus families cause characteristic neuroinvasive diseases in human populations. A complete understanding of the epidemiological and clinical features of the neuroinvasive arboviruses is important such that these pathogens can be recognized and diagnosed in humans as they emerge. Ongoing research to develop rapid, accurate diagnostics, therapeutic options and vaccines for these pathogens is needed to address future outbreaks of disease in human populations.

Characteristics and outcome of varicella-zoster virus central nervous system infections in adults.

We conducted an observational retrospective study of all adults hospitalized for documented varicella-zoster virus (VZV) meningitis or encephalitis during years 2000-2015 in one referral centre. Thirty-six patients (21 males, 15 females) were included, with meningitis (n = 21), or meningoencephalitis (n = 15). Median age was 51 years [interquartile range, 35-76], and 6 patients (17%) were immunocompromised. Aciclovir was started in 32 patients (89%), with a median dose of 11 mg/kg/8 h [10-15]. No patient died, but 12 (33%) had neurological sequelae at discharge. Age was the only variable associated with adverse outcome (OR 1.98 [1.17-3.35] per 10-year increment, P = 0.011).

Direct next-generation sequencing diagnosis of echovirus 9 meningitis, France.

The prognosis of central nervous system infections caused by enteroviruses partially depends on the viral genotype, which is not provided by current point-of-care diagnostic methods. In this study, next-generation sequencing identified an echovirus 9 directly from the cerebrospinal fluid of a patient presenting with meningitis.

Childhood Outcomes Following Parechovirus Infections in a US Young Infant Cohort.

BACKGROUND: Parechovirus A type 3 (PeV-A3) is associated with central nervous system infection in young infants. There are limited data regarding long-term outcomes, mostly reported from Australia and European populations. The objective of this study was to assess frequency of neurodevelopmental impairment (NDI) following PeV-A3 infection in our US cohort. METHODS: Infants hospitalized during the 2014 outbreak with laboratory-confirmed PeV-A3 infection were evaluated with medical history, neurologic examination, parental completion of Ages and Stages Questionnaire and developmental assessment using Bayley Scales of Infant and Toddler Development, Third Edition cognitive, motor and language quotients. Determination of NDI was based on published criteria. Relationship of severity of PeV disease to outcome measures was determined using Fisher exact, χ2 and Mann-Whitney U test as appropriate. RESULTS: Nineteen children, term gestation, were evaluated at ~3 years of age; PeV-A3 illness was uncomplicated for 6 (32%), complex, non-neurologic for 9 (47%) and encephalitis/seizures for 4 (21%). No differences were noted in mean Bayley Scales of Infant and Toddler Development, Third Edition quotients between infants by clinical presentation. Quotients for all were within 1 SD of population norms. Two (11%) children had mild NDI; 1 with mild cerebral palsy. Ages and Stages Questionnaire results included 11% at referral level and 37% suspect concern. Parents of 6 (32%) noted behavior concerns. These findings were unrelated to severity of the PeV-A3 illness. CONCLUSIONS: Parent concerns were identified frequently following infant PeV-A3 disease. Eleven percent had neurodevelopmental impairment at 3 years of age. Severity at presentation did not correlate with adverse childhood outcomes. Longitudinal developmental monitoring following infantile PeV-A3 disease is warranted.

The yield of CSF molecular testing in febrile neonates.

We retrospectively examined the yield of a cerebrospinal fluid (CSF) multiplex real-time PCR assay of febrile young infants undergoing a full sepsis work-up. Eighty infants were included in the study: Forty-nine (61%) neonates and 31 (39%) 29-90 day-old patients were included in the study. A viral pathogen was detected in 59% (47/80) of the samples, human enterovirus in 53% (42/80) and Human parechovirus in 6% (5/80). The CSF of nearly half of the subjects with CNS infection was without pleocytosis; all CSF cultures were negative. Multiplex PCR CSF testing enhances the diagnosis of pathogen-specific viral CNS infection among febrile young infants.

Pneumonia and central nervous system infection caused by reactivation of varicella-zoster virus in a living-donor kidney transplantation patient: case report and review of the literature.

Varicella-zoster virus (VZV) typically causes herpes zoster in the elderly due to reactivation, but immunocompromised individuals may develop organ damage such as pneumonia with a poor prognosis. We herein report a case of pneumonia and central nervous system (CNS) infection caused by reactivation of VZV in a 50-year-old man who had received a living-donor kidney transplant. We also conducted a literature review of adult cases with pneumonia or CNS infection caused by VZV after kidney transplantation. It showed that there are cases in which eruptions appeared upto 21 days after the onset of the disease and others in which eruptions did not appear at any time during the clinical course. Furthermore, there may be a wide variety of intervals from kidney transplantation to VZV infection (including both primary infection and reactivation of VZV), ranging from 2 weeks to 11 years. Therefore, it should be kept in mind that kidney transplant patients are always at high risk of VZV infection, as early recognition and treatment of the disease improves its prognosis. Although the diagnosis of varicella pneumonia is generally made by PCR test of bronchoalveolar lavage fluid, our case experience suggests that the less invasive PCR test of sputum may be useful for rapid and accurate diagnosis. The efficacy of inactivated recombinant zoster vaccine in immunocompromised individuals at high risk of reactivation of VZV also needs to be examined in the future.