Parechovirus Encephalitis and Neurodevelopmental Outcomes

Britton, Philip N; Dale, Russell C.; Nissen, Michael; Crawford, Nigel; Elliott, Elizabeth J; Macartney, Kristine; Khandaker, Gulam; Booy, Robert; Jones, Cheryl

doi:10.1542/peds.2015-2848

Cited by 117 publications

(118 citation statements)

References 61 publications

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“…This is based on the hypothesis that CSF cytokines may correspond to the intrathecal activation of immunoactive cells, and the evaluation of these cytokines might be a good indicator of the type of immune activation, the severity of inflammation and disease activity in neuroinflammatory disorders of the brain. In our cohort, among currently available investigations, the sensitivity of pleocytosis, oligoclonal bands and neopterin were similar to previous studies [4, 7, 9, 18, 19]. CSF neopterin performed the best of these commonly used CSF biomarkers, although is not used commonly in neurology practice outside of HIV neurology [20].…”

Section: Discussionsupporting

confidence: 88%

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

et al. 2016

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BackgroundDespite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications.AimTo study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis.MethodsWe measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups.ResultsIn descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α.ConclusionA combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis.

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Section: Discussionsupporting

confidence: 88%

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

et al. 2016

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“…This raises an important question about the need for longer term follow-up. Perhaps more concerning was a recent Australian report where, of 13 infants with severe HPeV encephalitis, 3 had sequelae at hospital discharge, and 5 of 8 infants at 12-month follow-up had neurodevelopmental complications, including 2 with cerebral palsy 11. In a previous UK case series, 3 of 19 infants with follow-up information had significant neurological sequelae 5.…”

Section: Discussionmentioning

confidence: 99%

Increased detection of human parechovirus infection in infants in England during 2016: epidemiology and clinical characteristics

et al. 2018

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“…The range and severity of clinical manifestations and prognosis of HPeV3 infection is not well defined. In a group of 10 infants with HPeV3 CNS infection, evaluation by cranial magnetic resonance imaging (MRI) or ultrasound showed abnormal periventricular white matter in all infants and in a number of the infants clinical follow-up revealed sequelae including cerebral palsy, epilepsy, learning disabilities, and visual impairment3940. Further cases like this are referenced in ref.…”

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An outbreak of severe infections among Australian infants caused by a novel recombinant strain of human parechovirus type 3

Nelson

Vuillermin

Hodge

et al. 2017

Sci Rep

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Human parechovirus types 1–16 (HPeV1–16) are positive strand RNA viruses in the family Picornaviridae. We investigated a 2015 outbreak of HPeV3 causing illness in infants in Victoria, Australia. Virus genome was extracted from clinical material and isolates and sequenced using a combination of next generation and Sanger sequencing. The HPeV3 outbreak genome was 98.7% similar to the HPeV3 Yamagata 2011 lineage for the region encoding the structural proteins up to nucleotide position 3115, but downstream of that the genome varied from known HPeV sequences with a similarity of 85% or less. Analysis indicated that recombination had occurred, may have involved multiple types of HPeV and that the recombination event/s occurred between March 2012 and November 2013. However the origin of the genome downstream of the recombination site is unknown. Overall, the capsid of this virus is highly conserved, but recombination provided a different non-structural protein coding region that may convey an evolutionary advantage. The indication that the capsid encoding region is highly conserved at the amino acid level may be helpful in directing energy towards the development of a preventive vaccine for expecting mothers or antibody treatment of young infants with severe disease.

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Parechovirus Encephalitis and Neurodevelopmental Outcomes

Abstract: on behalf of the PAEDS-ACE Investigators abstract OBJECTIVE: We aimed to describe the clinical features and outcome of human parechovirus (HPeV) encephalitis cases identified by the Australian Childhood Encephalitis (ACE) study.

Cited by 117 publications

References 61 publications

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

Increased detection of human parechovirus infection in infants in England during 2016: epidemiology and clinical characteristics

An outbreak of severe infections among Australian infants caused by a novel recombinant strain of human parechovirus type 3

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