Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vß21.3+ activation in multi-inflammatory syndrome in children.

Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vß21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vß21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vß21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells.

Profiling gut microbiota and bile acid metabolism in critically ill children.

Broad-spectrum antimicrobial use during the treatment of critical illness influences gastrointestinal fermentation endpoints, host immune response and metabolic activity including the conversion of primary to secondary bile acids. We previously observed reduced fermentation capacity in the faecal microbiota of critically ill children upon hospital admission. Here, we further explore the timecourse of the relationship between the microbiome and bile acid profile in faecal samples collected from critically ill children. The microbiome was assayed by sequencing of the 16S rRNA gene, and faecal water bile acids were measured by liquid chromatography mass spectrometry. In comparison to admission faecal samples, members of the Lachnospiraceae recovered during the late-acute phase (days 8-10) of hospitalisation. Patients with infections had a lower proportion of Lachnospiraceae in their gut microbiota than controls and patients with primary admitting diagnoses. Keystone species linked to ecological recovery were observed to decline with the length of PICU admission. These species were further suppressed in patients with systemic infection, respiratory failure, and undergoing surgery. Bile acid composition recovers quickly after intervention for critical illness which may be aided by the compositional shift in Lachnospiraceae. Our findings suggest gut microbiota recovery can be readily assessed via measurement of faecal bile acids.

Characteristics of adolescents requiring intensive care in the United Kingdom: A retrospective cohort study.

OBJECTIVES: To describe the case mix, resource use and outcomes for adolescents admitted to intensive care units in the UK. METHODS: Analysis of national prospectively collected data for all adolescents aged 12-19 years admitted to UK adult or paediatric intensive care units. RESULTS: There were 37,320 admissions of adolescents during the eight-year study period. Excluding elective surgery, respiratory diagnoses were the most common reason for paediatric intensive care unit (PICU) admission, with trauma and intoxication the most common reasons for adult intensive care unit (AICU) admission. Intensive care unit mortality was 6.0% and 5.7% for those admitted to PICUs and AICUs, respectively. CONCLUSIONS: Mortality is similar among adolescents admitted to AICUs and PICUs; however, these rates have not been corrected for severity of acute illness or underlying burden of chronic illness, which may be different between AICUs and PICUs. Services planned for the majority of AICU and PICU patients may not be optimal for critically ill adolescents treated in UK intensive care units, who may need special consideration.

Inter-hospital transport of the child with critical cardiac disease.

Centralisation of services such as cardiology, cardiac surgery, and intensive care in many parts of the world has resulted in the need to safely transport children with critical cardiac disease from local hospitals to specialist centres for diagnostic, surgical, and/or critical care intervention. The transport of this cohort of children, whether locally or internationally, can present specific clinical and logistical challenges. An international group of clinicians with expertise in cardiac care and critical care transport worked together to summarise current clinical practice relating to key areas of transport. This expert review covers the transport of the child with critical cardiac disease in terms of referral triage and advice, enabling optimal management of locally available resources, clinical stabilisation before transport, international air transport, transport considerations in low- and middle-income countries, and the transport of children with specific cardiac conditions. As specialist services are centralised to fewer large centres, the need for safe and timely inter-hospital transport of children with critical cardiac disease is only expected to rise in the future. The key principles outlined in this review will be helpful for practitioners in global settings who are, or might be, involved in transporting children between hospitals.

Outcomes for Children Receiving Noninvasive Ventilation as the First-Line Mode of Mechanical Ventilation at Intensive Care Admission: A Propensity Score-Matched Cohort Study.

OBJECTIVES: To compare outcomes of children receiving noninvasive ventilation with those receiving invasive ventilation as first-line mode of mechanical ventilation following unplanned intensive care admission. DESIGN: Propensity score-matched cohort study analyzing data prospectively collected by the Pediatric Intensive Care Audit Network over 8 years (2007-2014). SETTING: Thirty-one PICUs in the United Kingdom and Ireland; twenty-one of whom submitted Pediatric Critical Care Minimum Dataset data for the entire study period. PATIENTS: Children consecutively admitted to study PICUs. Planned admissions following surgery, unplanned admissions from other hospitals, those on chronic ventilation, and those who did not receive mechanical ventilation on the day of PICU admission were excluded. INTERVENTIONS: Use of noninvasive ventilation, rather than invasive ventilation, as the first-line mode of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: PICU mortality, length of ventilation, length of PICU stay, and ventilator-free days at day 28. During the study period, there were 151,128 PICU admissions. A total of 15,144 admissions (10%) were eligible for analysis once predefined exclusion criteria were applied: 4,804 (31.7%) received "noninvasive ventilation first," whereas 10,221 (67.5%) received "invasive ventilation first"; 119 (0.8%) admissions could not be classified. Admitting PICU site explained 6.5% of the variation in first-line mechanical ventilation group (95% CI, 2.0-19.0%). In propensity score-matched analyses, receiving noninvasive ventilation first was associated with a significant reduction in mortality by 3.1% (95% CI, 1.7-4.6%), length of ventilation by 1.6 days (95% CI, 1.0-2.3), and length of PICU stay by 2.1 days (95% CI, 1.3-3.0), as well as an increase in ventilator-free days at day 28 by 3.7 days (95% CI, 3.1-4.3). CONCLUSIONS: Use of noninvasive ventilation as first-line mode of mechanical ventilation in critically ill children admitted to PICU in an unplanned fashion may be associated with significant clinical benefits. Further high-quality evidence regarding optimal patient selection and timing of initiation of noninvasive ventilation could lead to less variability in clinical care between institutions and improved patient outcomes.

Characteristics of deaths occurring in hospitalised children: changing trends.

BACKGROUND: Despite a gradual shift in the focus of medical care among terminally ill patients to a palliative model, studies suggest that many children with life-limiting chronic illnesses continue to die in hospital after prolonged periods of inpatient admission and mechanical ventilation. OBJECTIVES: To (1) examine the characteristics and location of death among hospitalised children, (2) investigate yearwise trends in these characteristics and (3) test the hypothesis that professional ethical guidance from the UK Royal College of Paediatrics and Child Health (1997) would lead to significant changes in the characteristics of death among hospitalised children. METHODS: Routine administrative data from one large tertiary-level UK children's hospital was examined over a 7-year period (1997-2004) for children aged 0-18 years. Demographic details, location of deaths, source of admission (within hospital vs external), length of stay and final diagnoses (International Classification of Diseases-10 codes) were studied. Statistical significance was tested by the Kruskal-Wallis analysis of ranks and median test (non-parametric variables), chi(2) test (proportions) and Cochran-Armitage test (linear trends). RESULTS: Of the 1127 deaths occurring in hospital over the 7-year period, the majority (57.7%) were among infants. The main diagnoses at death included congenital malformations (22.2%), perinatal diseases (18.1%), cardiovascular disorders (14.9%) and neoplasms (12.4%). Most deaths occurred in an intensive care unit (ICU) environment (85.7%), with a significant increase over the years (80.1% in 1997 to 90.6% in 2004). There was a clear increase in the proportion of admissions from in-hospital among the ICU cohort (14.8% in 1998 to 24.8% in 2004). Infants with congenital malformations and perinatal conditions were more likely to die in an ICU (OR 2.42, 95% CI 1.65 to 3.55), and older children with malignancy outside the ICU (OR 6.5, 95% CI 4.4 to 9.6). Children stayed for a median of 13 days (interquartile range 4.0-23.25 days) on a hospital ward before being admitted to an ICU where they died. CONCLUSIONS: A greater proportion of hospitalised children are dying in an ICU environment. Our experience indicates that professional ethical guidance by itself may be inadequate in reversing the trends observed in this study.