Fifteen minute consultation: Managing neonatal and childhood herpes encephalitis

Herpes simplex encephalitis (HSE) is the most common single cause of viral encephalitis in infants and children. Treated or untreated, it can be associated with considerable morbidity and mortality, and its presentation is usually insidious and non-specific. Prompt and careful investigation is important in order to establish the diagnosis so that treatment can be optimised. We address some common questions arising when diagnosing and treating presumed HSE throughout childhood

Lymphocyte subpopulations in premature infants: An observational study

Background and objectives The infant's immune system evolves over the first months and years of life. Strong correlation exists between lymphocyte count, lymphocyte subpopulations and gestational age at birth. Associations with antenatal and postnatal steroid treatment, infection and chronic lung disease have also been described. Few published studies report the effect of increasing postnatal age (PNA) and comorbidities on lymphocyte subpopulations in premature infants beyond the first 4 months of life. This study aimed to describe changes in lymphocyte subpopulations in preterm infants up to 13 months PNA. Methods Premature infants (23–34 weeks completed gestation) from five centres had lymphocyte subpopulations measured at 2, 5 or 7, 12 and 13 months PNA alongside their vaccine responses in a vaccination trial. Results 393 blood samples from 151 babies were analysed. There was an increase in absolute numbers of total lymphocytes (median cell count 6.21×109/L at 13 months compared with 4.9×109/L at 2 months PNA) and CD3+, CD4+, CD8+, natural killer and B cells with increasing age. At 2 months PNA, there was a positive correlation between gestation and CD3+ and CD4+ counts (r=0.32 and 0.46, respectively) and proportions (r=0.22 and 0.41, respectively), and CD4+:CD8+ ratios (r=0.57), but a negative correlation with CD8+ proportions (r=−0.32). Conclusions This longitudinal study describes the distribution of lymphocyte subpopulations in premature infants and provides reference ranges for the major lymphocyte subsets to help guide clinicians when assessing premature infants for immunodeficiency in the first year of life. Trial registration number EudraCT 2007-007535-23

Using a simple point-prevalence survey to define appropriate antibiotic prescribing in hospitalised children across the UK.

BACKGROUND: The National Health Service England, Commissioning for Quality and Innovation for Antimicrobial Resistance (CQUIN AMR) aims to reduce the total antibiotic consumption and the use of certain broad-spectrum antibiotics in secondary care. However, robust baseline antibiotic use data are lacking for hospitalised children. In this study, we aim to describe, compare and explain the prescription patterns of antibiotics within and between paediatric units in the UK and to provide a baseline for antibiotic prescribing for future improvement using CQUIN AMR guidance. METHODS: We conducted a cross-sectional study using a point prevalence survey (PPS) in 61 paediatric units across the UK. The standardised study protocol from the Antibiotic Resistance and Prescribing in European Children (ARPEC) project was used. All inpatients under 18 years of age present in the participating hospital on the day of the study were included except neonates. RESULTS: A total of 1247 (40.9%) of 3047 children hospitalised on the day of the PPS were on antibiotics. The proportion of children receiving antibiotics showed a wide variation between both district general and tertiary hospitals, with 36.4% ( 95% CI 33.4% to 39.4%) and 43.0% (95% CI 40.9% to 45.1%) of children prescribed antibiotics, respectively. About a quarter of children on antibiotic therapy received either a medical or surgical prophylaxis with parenteral administration being the main prescribed route for antibiotics (>60% of the prescriptions for both types of hospitals). General paediatrics units were surprisingly high prescribers of critical broad-spectrum antibiotics, that is, carbapenems and piperacillin-tazobactam. CONCLUSIONS: We provide a robust baseline for antibiotic prescribing in hospitalised children in relation to current national stewardship efforts in the UK. Repeated PPS with further linkage to resistance data needs to be part of the antibiotic stewardship strategy to tackle the issue of suboptimal antibiotic use in hospitalised children

A Feasibility Study of Quantifying Longitudinal Brain Changes in Herpes Simplex Virus (HSV) Encephalitis Using Magnetic Resonance Imaging (MRI) and Stereology.

OBJECTIVES: To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid therapy. METHODS: The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting. RESULTS: Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids. CONCLUSIONS: This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis

Height and timing of growth spurt during puberty in young people living with vertically acquired HIV in Europe and Thailand.

OBJECTIVE: The aim of this study was to describe growth during puberty in young people with vertically acquired HIV. DESIGN: Pooled data from 12 paediatric HIV cohorts in Europe and Thailand. METHODS: One thousand and ninety-four children initiating a nonnucleoside reverse transcriptase inhibitor or boosted protease inhibitor based regimen aged 1-10 years were included. Super Imposition by Translation And Rotation (SITAR) models described growth from age 8 years using three parameters (average height, timing and shape of the growth spurt), dependent on age and height-for-age z-score (HAZ) (WHO references) at antiretroviral therapy (ART) initiation. Multivariate regression explored characteristics associated with these three parameters. RESULTS: At ART initiation, median age and HAZ was 6.4 [interquartile range (IQR): 2.8, 9.0] years and -1.2 (IQR: -2.3 to -0.2), respectively. Median follow-up was 9.1 (IQR: 6.9, 11.4) years. In girls, older age and lower HAZ at ART initiation were independently associated with a growth spurt which occurred 0.41 (95% confidence interval 0.20-0.62) years later in children starting ART age 6 to 10 years compared with 1 to 2 years and 1.50 (1.21-1.78) years later in those starting with HAZ less than -3 compared with HAZ at least -1. Later growth spurts in girls resulted in continued height growth into later adolescence. In boys starting ART with HAZ less than -1, growth spurts were later in children starting ART in the oldest age group, but for HAZ at least -1, there was no association with age. Girls and boys who initiated ART with HAZ at least -1 maintained a similar height to the WHO reference mean. CONCLUSION: Stunting at ART initiation was associated with later growth spurts in girls. Children with HAZ at least -1 at ART initiation grew in height at the level expected in HIV negative children of a comparable age

6-OHDA-induced dopaminergic neurodegeneration in <i>Caenorhabditis elegans</i> is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33

<div><p>Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson’s disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting <i>Caenorhabditis elegans</i> dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the <u>t</u>rans<u>t</u>hyretin-<u>r</u>elated gene <i>ttr-33</i>. The only described <i>C</i>. <i>elegans</i> transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of <i>C</i>. <i>elegans</i> larvae and is predicted to be a secreted protein. TTR-33 protects <i>C</i>. <i>elegans</i> from oxidative stress induced by paraquat or H₂O₂ at an organismal level. The increased oxidative stress sensitivity of <i>ttr-33</i> mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the <i>C</i>. <i>elegans</i> cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.</p></div

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch