The plasma proteome differentiates the multisystem inflammatory syndrome in children (MIS-C) from children with SARS-CoV-2 negative sepsis.

BACKGROUND: The Multi-System Inflammatory Syndrome in Children (MIS-C) can develop several weeks after SARS-CoV-2 infection and requires a distinct treatment protocol. Distinguishing MIS-C from SARS-CoV-2 negative sepsis (SCNS) patients is important to quickly institute the correct therapies. We performed targeted proteomics and machine learning analysis to identify novel plasma proteins of MIS-C for early disease recognition. METHODS: A case-control study comparing the expression of 2,870 unique blood proteins in MIS-C versus SCNS patients, measured using proximity extension assays. The 2,870 proteins were reduced in number with either feature selection alone or with a prior COMBAT-Seq batch effect adjustment. The leading proteins were correlated with demographic and clinical variables. Organ system and cell type expression patterns were analyzed with Natural Language Processing (NLP). RESULTS: The cohorts were well-balanced for age and sex. Of the 2,870 unique blood proteins, 58 proteins were identified with feature selection (FDR-adjusted P < 0.005, P < 0.0001; accuracy = 0.96, AUC = 1.00, F1 = 0.95), and 15 proteins were identified with a COMBAT-Seq batch effect adjusted feature selection (FDR-adjusted P < 0.05, P < 0.0001; accuracy = 0.92, AUC = 1.00, F1 = 0.89). All of the latter 15 proteins were present in the former 58-protein model. Several proteins were correlated with illness severity scores, length of stay, and interventions (LTA4H, PTN, PPBP, and EGF; P < 0.001). NLP analysis highlighted the multi-system nature of MIS-C, with the 58-protein set expressed in all organ systems; the highest levels of expression were found in the digestive system. The cell types most involved included leukocytes not yet determined, lymphocytes, macrophages, and platelets. CONCLUSIONS: The plasma proteome of MIS-C patients was distinct from that of SCNS. The key proteins demonstrated expression in all organ systems and most cell types. The unique proteomic signature identified in MIS-C patients could aid future diagnostic and therapeutic advancements, as well as predict hospital length of stays, interventions, and mortality risks.

In situ simulation training for parental presence during critical situations in PICU: an observational study.

Family presence during invasive procedures or cardiopulmonary resuscitation (CPR) is a part of the family-centered approach in pediatric intensive care units (PICUs). We established a simulation program aiming at providing communication tools to healthcare professionals. The goal of this study was to evaluate the impact of this program on the stress of PICU professionals and its acceptance. An observational study of a simulation program, with questionnaire, was used to measure pre- and post-simulation stress and the degree of satisfaction of the participants. PICU of Geneva Children's Hospital, Switzerland. Forty simulations with four different simulation scenarios and various types of parental behavior, as imitated by professional actors, were completed during a 1-year period. Primary outcomes were the difference in perceived stress level before and after the simulation and the degree of satisfaction of healthcare professionals (nursing assistants, nurses, physicians). The impact of previous experience with family members during critical situations or CPR was evaluated by variation in perceived stress level. Overall, 201 questionnaires were analyzed. Perceived stress associated with parental presence decreased from a pre-simulation value of 6 (IQR, 4-7) to 4 (IQR, 2-5) post-simulation on a scale of 1-10. However, in 25.7% of cases, the individually perceived post-simulation stress level was higher than the pre-simulation one. Satisfaction of the participants was high with a median of 10 (IQR, 9-10) out of 10. CONCLUSIONS: A simulation program helps reduce PICU team emotional stress associated with the presence of family members during critical situations or CPR, and is welcomed by PICU team members. WHAT IS KNOWN: • Family presence during cardiopulmonary resuscitation (CPR) or critical situations is a part of the family-centered approach in pediatric intensive care. • The benefits for the family have been already demonstrated. However, this policy is still controversy among healthcare professionals. WHAT IS NEW: • A simulation program seeking to provide skills focused on family presence management in the PICU is useful to reduce stress and was well accepted by participants. • It might become an indispensable training intervention for the implementation of a PICU policy to allow family presence during CPR or other critical situations.

Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

BACKGROUND: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. METHODS: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. RESULTS: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). CONCLUSION: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

Alveolar CCN1 is associated with mechanical stretch and acute respiratory distress syndrome severity.

The cellular communication network factor 1 (CCN1) is a matricellular protein that can modulate multiple tissue responses, including inflammation and repair. We have previously shown that adenoviral overexpression of Ccn1 is sufficient to cause acute lung injury in mice. We hypothesized that CCN1 is present in the airspaces of lungs during the acute phase of lung injury, and higher concentrations are associated with acute respiratory distress syndrome (ARDS) severity. We tested this hypothesis by measuring 1) CCN1 in bronchoalveolar lavage fluid (BALF) and lung homogenates from mice subjected to ventilation-induced lung injury (VILI), 2) Ccn1 gene expression and protein levels in MLE-12 cells (alveolar epithelial cell line) subjected to mechanical stretch, and 3) CCN1 in BALF from mechanically ventilated humans with and without ARDS. BALF CCN1 concentrations and whole lung CCN1 protein levels were significantly increased in mice with VILI (n = 6) versus noninjured controls (n = 6). Ccn1 gene expression and CCN1 protein levels were increased in MLE-12 cells cultured under stretch conditions. Subjects with ARDS (n = 77) had higher BALF CCN1 levels compared with mechanically ventilated subjects without ARDS (n = 45) (P < 0.05). In subjects with ARDS, BALF CCN1 concentrations were associated with higher total protein, sRAGE, and worse [Formula: see text]/[Formula: see text] ratios (all P < 0.05). CCN1 is present in the lungs of mice and humans during the acute inflammatory phase of lung injury, and concentrations are higher in patients with increased markers of severity. Alveolar epithelial cells may be an important source of CCN1 under mechanical stretch conditions.

Human Deoxyribonuclease (rhDNase) Nebulization as an Alternative Treatment for Refractory Plastic Bronchitis After Fontan Surgery.

We report the case of a 5-year-old boy who developed chronic plastic bronchitis after Fontan surgery for a complex congenital heart disease. During a new admission for acute exacerbation of plastic bronchitis, he started on a mucolytic treatment with inhaled rhDNAse instead of inhaled fibrinolytics because of the potential bleeding risk in a patient on combined coumarin and aspirin treatment. Respiratory symptoms resolved promptly, and the patient was discharged home on rhDNAse treatment. He remained clinically stable on rhDNAse treatment without further hospitalization until definitive treatment with dynamic lymphangiography and percutaneous embolization.

IRAK-4 deficiency as a cause for familial fatal invasive infection by Streptococcus pneumoniae.

In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4. The letter also highlights the importance of invasive pneumococcal infection as a critical 'red flag' warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency.

Phenotypic expansion of TBX4 mutations to include acinar dysplasia of the lungs.

Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc.

CYR61 (CCN1) overexpression induces lung injury in mice.

Cysteine-rich protein-61 (CYR61), also known as connective tissue growth factor, CYR61, and nephroblastoma overexpressed gene 1 (CCN1), is a heparin-binding protein member of the CCN family of matricellular proteins. Gene expression profiles showed that Cyr61 is upregulated in human acute lung injury (ALI), but its functional role is unclear. We hypothesized that CYR61 contributes to ALI in mice. First, we demonstrated that CYR61 expression increases after bleomycin-induced lung injury. We then used adenovirus-mediated gene transfer to determine whether CYR61 overexpression in the lungs was sufficient to cause ALI. Mice instilled with CYR61 adenovirus showed greater weight loss, increased bronchoalveolar lavage total neutrophil counts, increased protein concentrations, and increased mortality compared with mice instilled with empty-vector adenovirus. Immunohistochemical studies in lungs from humans with idiopathic pulmonary fibrosis revealed CYR61 expression on the luminal membrane of alveolar epithelial cells in areas of injury. We conclude that CYR61 is upregulated in ALI and that CYR61 overexpression exacerbates ALI in mice.

Extracorporeal Membrane Oxygenation After Liver Transplant in Children: A Review of the ELSO Registry.

There are minimal data describing use of extracorporeal membrane oxygenation (ECMO) in pediatric patient after a liver transplantation (LT). This study aimed at describing ECMO run in this specific situation using the data from Extracorporeal Life Support Organization (ELSO) Registry between January 1, 2010, to December 31, 2022. We described patients' characteristics at ECMO initiation, outcome and mortality risk factors. We identified 27 patients with a median age of 2.7 years (interquartile range (IQR) = 1.5-9.9). Main indication for ECMO support was respiratory (14/27 [52%]) followed by extracorporeal cardiopulmonary resuscitation (ECPR) (7/27 [26%]) and cardiac (6/27 [22%]). Overall in-hospital mortality was 63% (17/27). Mortality rate according to ECMO indications was 50% for both respiratory and cardiac failure and reached 100% for ECPR patients. Overall, nonsurvivors experienced significantly more complications under ECMO support ( p = 0.007). Main on-ECMO complications were hemorrhagic (11/27 [41%]) and thrombotic (7/27 [26%]). No clinical or biologic factors was predictive of patients' outcome. Our results suggest that ECMO support is a viable option for cardiac and respiratory indications after pediatric LT. Occurrence of complications while on ECMO are associated with unfavorable outcomes. The extremely high mortality rate in ECPR patients merits further research.

COVID-19 Vaccine Acceptance Among Parents of Children With Multisystem Inflammatory Syndrome in Children.

Data on COVID-19 vaccine acceptability among parents of children with multisystem inflammatory syndrome (MIS-C) are limited. In this cohort of children with MIS-C, enrolled in the Swissped RECOVERY trial (NCT04826588), comparing intravenous immunoglobulins or methylprednisolone, who, in accordance with Swiss guidelines, were recommended for SARS-CoV-2 vaccination, 65% (73/112) of parents reported being vaccinated against SARS-CoV-2 before the MIS-C, while 70% were vaccinated after the MIS-C episode of their child. None of the children were vaccinated before the occurrence of the MIS-C, and only 9% (5/56) received the COVID-19 vaccine after the MIS-C. The predominant barriers to COVID-19 vaccination were concerns over potential side effects and insufficient support from their doctors. This emphasizes the crucial role of health care providers in promoting COVID-19 vaccination among children.

Cardiac assessment and inflammatory markers in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV2 (PIMS-TS) treated with methylprednisolone versus intravenous immunoglobulins: 6-month follow-up outcomes of the randomised controlled Swissped RECOVERY trial.

Background: Previous findings from the Swissped RECOVERY trial showed that patients with Pediatric Inflammatory Multisystem Syndrome-Temporally Associated with SARS-CoV-2 (PIMS-TS) who were randomly assigned to intravenous immunoglobulins or methylprednisolone have a comparable length of hospital stay. Here, we report the 6-month follow-up outcomes of cardiac pathologies and normalisation of clinical or laboratory signs of inflammation from this study population. Methods: This pre-planned follow-up of patients with PIMS-TS included the Swissped RECOVERY Trial reports on the 6-month outcomes of the cohort after randomisation, with a focus on cardiac, haematological, and biochemical findings. The trial was an investigator-initiated randomised multicentre open-label two-arm trial in children and adolescents hospitalised with PIMS-TS at ten hospitals in Switzerland. Cardiological assessments and laboratory analyses were prospectively collected in the intention-to-treat analysis on pre-defined intervals after hospital discharge. Differences between randomised arms were investigated using Chi-square test for categorical and Wilcoxon test for continuous variables. The trial is registered with the Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). Findings: Between May 21, 2021 and April 15, 2022, 75 patients with a median age of 9.1 years (IQR 6.2-12.2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulin group). During follow-up, the incidence of abnormal left ventricular systolic function, coronary artery aneurysms (CAA), and other signs of inflammation were comparable in both groups. However, we detected cardiac abnormalities with low incidence and a mild degree grade of pathology. CAAs were observed in 2/38 children (5.3%) in the IVIG group and 1/37 children (2.7%) in the methylprednisolone group at 6-month follow-up (difference proportion 0.75; 95% confidence interval (CI) -0.05 to 1.0; p = 0.39). Interpretation: Methylprednisolone alone may be an acceptable first-line treatment as left ventricular systolic dysfunction and clinical/laboratory evidence for inflammation quickly resolved in all children. However, our findings need further confirmation through larger studies as our sample size is likely to be of insufficient power to address rare clinically relevant adverse outcomes. Funding: NOMIS, Vontobel, and Gaydoul Foundation.

Patient-ventilator asynchrony during noninvasive pressure support ventilation and neurally adjusted ventilatory assist in infants and children.

OBJECTIVES: To document the prevalence of asynchrony events during noninvasive ventilation in pressure support in infants and in children and to compare the results with neurally adjusted ventilatory assist. DESIGN: Prospective randomized cross-over study in children undergoing noninvasive ventilation. SETTING: The study was performed in a PICU. PATIENTS: From 4 weeks to 5 years. INTERVENTIONS: Two consecutive ventilation periods (pressure support and neurally adjusted ventilatory assist) were applied in random order. During pressure support (PS), three levels of expiratory trigger (ETS) setting were compared: initial ETS (PSinit), and ETS value decreased and increased by 15%. Of the three sessions, the period allowing for the lowest number of asynchrony events was defined as PSbest. Neurally adjusted ventilator assist level was adjusted to match the maximum airway pressure during PSinit. Positive end-expiratory pressure was the same during pressure support and neurally adjusted ventilator assist. Asynchrony events, trigger delay, and cycling-off delay were quantified for each period. RESULTS: Six infants and children were studied. Trigger delay was lower with neurally adjusted ventilator assist versus PSinit and PSbest (61 ms [56-79] vs 149 ms [134-180] and 146 ms [101-162]; p = 0.001 and 0.02, respectively). Inspiratory time in excess showed a trend to be shorter during pressure support versus neurally adjusted ventilator assist. Main asynchrony events during PSinit were autotriggering (4.8/min [1.7-12]), ineffective efforts (9.9/min [1.7-18]), and premature cycling (6.3/min [3.2-18.7]). Premature cycling (3.4/min [1.1-7.7]) was less frequent during PSbest versus PSinit (p = 0.059). The asynchrony index was significantly lower during PSbest versus PSinit (40% [28-65] vs 65.5% [42-76], p < 0.001). With neurally adjusted ventilator assist, all types of asynchronies except double triggering were reduced. The asynchrony index was lower with neurally adjusted ventilator assist (2.3% [0.7-5] vs PSinit and PSbest, p < 0.05 for both comparisons). CONCLUSION: Asynchrony events are frequent during noninvasive ventilation with pressure support in infants and in children despite adjusting the cycling-off criterion. Compared with pressure support, neurally adjusted ventilator assist allows improving patient-ventilator synchrony by reducing trigger delay and the number of asynchrony events. Further studies should determine the clinical impact of these findings.

Optimizing patient-ventilator synchrony during invasive ventilator assist in children and infants remains a difficult task*.

OBJECTIVES: To document and compare the prevalence of asynchrony events during invasive-assisted mechanical ventilation in pressure support mode and in neurally adjusted ventilatory assist in children. DESIGN: Prospective, randomized, and crossover study. SETTING: Pediatric and Neonatal Intensive Care Unit, University Hospital of Geneva, Switzerland. PATIENTS: Intubated and mechanically ventilated children, between 4 weeks and 5 years old. INTERVENTIONS: Two consecutive ventilation periods (pressure support and neurally adjusted ventilatory assist) were applied in random order. During pressure support, three levels of expiratory trigger setting were compared: expiratory trigger setting as set by the clinician in charge (PSinit), followed by a 10% (in absolute values) increase and decrease of the clinician's expiratory trigger setting. The pressure support session with the least number of asynchrony events was defined as PSbest. Therefore, three periods were compared: PSinit, PSbest, and neurally adjusted ventilatory assist. Asynchrony events, trigger delay, and inspiratory time in excess were quantified for each of them. MEASUREMENTS AND MAIN RESULTS: Data from 19 children were analyzed. Main asynchrony events during PSinit were autotriggering (3.6 events/min [0.7-8.2]), ineffective efforts (1.2/min [0.6-5]), and premature cycling (3.5/min [1.3-4.9]). Their number was significantly reduced with PSbest: autotriggering 1.6/min (0.2-4.9), ineffective efforts 0.7/min (0-2.6), and premature cycling 2/min (0.1-3.1), p < 0.005 for each comparison. The median asynchrony index (total number of asynchronies/triggered and not triggered breaths ×100) was significantly different between PSinit and PSbest: 37.3% [19-47%] and 29% [24-43%], respectively, p < 0.005). With neurally adjusted ventilatory assist, all types of asynchrony events except double-triggering and inspiratory time in excess were significantly reduced resulting in an asynchrony index of 3.8% (2.4-15%) (p < 0.005 compared to PSbest). CONCLUSIONS: Asynchrony events are frequent during pressure support in children despite adjusting the cycling off criteria. Neurally adjusted ventilatory assist allowed for an almost ten-fold reduction in asynchrony events. Further studies should determine the clinical impact of these findings.

Antibody response in children with multisystem inflammatory syndrome related to COVID-19 (MIS-C) compared to children with uncomplicated COVID-19.

Objectives: To comprehensively analyze the quality of the antibody response between children with Multisystem inflammatory syndrome (MIS-C) and age-matched controls at one month after SARS-CoV-2 exposure, and infected in the same time-period. Methods: Serum from 20 MIS-C children at admission, and 14 control children were analyzed. Antigen specific antibody isotypes and subclasses directed against various antigens of SARS-CoV-2 as well as against human common coronavirus (HCoVs) and commensal or pathogenic microorganisms were assessed by a bead-based multiplexed serological assay and by ELISA. The functionality of these antibodies was also assessed using a plaque reduction neutralization test, a RBD-specific avidity assay, a complement deposition assay and an antibody-dependent neutrophil phagocytosis (ADNP) assay. Results: Children with MIS-C developed a stronger IgA antibody response in comparison to children with uncomplicated COVID-19, while IgG and IgM responses are largely similar in both groups. We found a typical class-switched antibody profile with high level of IgG and IgA titers and a measurable low IgM due to relatively recent SARS-CoV-2 infection (one month). SARS-CoV-2-specific IgG antibodies of MIS-C children had higher functional properties (higher neutralization activity, avidity and complement binding) as compared to children with uncomplicated COVID-19. There was no difference in the response to common endemic coronaviruses between both groups. However, MIS-C children had a moderate increase against mucosal commensal and pathogenic strains, reflecting a potential association between a disruption of the mucosal barrier with the disease. Conclusion: Even if it is still unclear why some children develop a MIS-C, we show here that MIS-C children produce higher titers of IgA antibodies, and IgG antibodies with higher functionality, which could reflect the local gastro-intestinal mucosal inflammation potentially induced by a sustained SARS-CoV-2 gut infection leading to continuous release of SARS-CoV-2 antigens.

Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial.

BACKGROUND: The emergence of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) led to the widespread use of anti-inflammatory treatments in the absence of evidence from randomised controlled trials (RCTs). We aimed to assess the effectiveness of intravenous methylprednisolone compared with intravenous immunoglobulins. METHODS: This is an open-label, multicentre, two-arm RCT done at ten hospitals in Switzerland in children younger than 18 years hospitalised with PIMS-TS (defined as age <18 years; fever and biochemical evidence of inflammation, and single or multiorgan dysfunction; microbiologically proven or putative contact with SARS-CoV-2; and exclusion of any other probable disease). Patients were randomly assigned 1:1 to intravenous methylprednisolone (10 mg/kg per day for 3 days) or intravenous immunoglobulins (2 g/kg as a single dose). The primary outcome was length of hospital stay censored at day 28, death, or discharge. Secondary outcomes included proportion and duration of organ support. Analyses were done by intention-to-treat. The study was registered with Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS: Between May 21, 2021, and April 15, 2022, 75 patients with a median age of 9·1 years (IQR 6·2-12·2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulins group). The median length of hospital stay was 6·0 days (IQR 4·0-8·0) in the methylprednisolone group and 6·0 days (IQR 5·0-8·8) in the intravenous immunoglobulins group (estimated effect size -0·037 of the log10 transformed times, 95% CI -0·13 to 0·065, p=0·42). Fewer patients in the methylprednisolone group (ten [27%] of 37) required respiratory support compared with the intravenous immunoglobulin group (21 [55%] of 38, p=0·025). Need and duration of inotropes, admission to intensive care units, cardiac events after baseline, and major bleeding and thrombotic events were not significantly different between the study groups. INTERPRETATION: In this RCT, treatment with methylprednisolone in children with PIMS-TS did not significantly affect the length of hospital stay compared with intravenous immunoglobulins. Intravenous methylprednisolone could be an acceptable first-line treatment in children with PIMS-TS. FUNDING: NOMIS Foundation, Vontobel Foundation, and Gaydoul Foundation.

Advances in medical management of acute liver failure in children: promoting native liver survival.

Paediatric acute liver failure (PALF) is defined as a biochemical evidence of acute liver injury in a child with no previous history of chronic liver disease characterised by an international normalised ratio (INR) of 1·5 or more unresponsive to vitamin K with encephalopathy, or INR of 2·0 or more with or without encephalopathy. PALF can rapidly progress to multiorgan dysfunction or failure. Although the transplant era has substantially changed the outlook for these patients, transplantation itself is not without risks, including those associated with life-long immunosuppression. Consequently, there has been an increased focus on improving medical management to prioritise bridging of patients to native liver survival, which is possible due to improved understanding of the underlying pathophysiology of multiorgan involvement in PALF. In this Review, we discuss recent advances in the medical management of PALF with an aim of reducing the need for liver transplantation. The Review will focus on the non-specific immune-mediated inflammatory response, extracorporeal support devices, neuromonitoring and neuroprotection, and emerging cellular and novel future therapeutic options.

The SARS-CoV-2 Pandemic Impacts the Management of Swiss Pediatric Intensive Care Units.

The impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic on pediatric intensive care units (PICUs) is difficult to quantify. We conducted an observational study in all eight Swiss PICUs between 02/24/2020 and 06/15/2020 to characterize the logistical and medical aspects of the pandemic and their impact on the management of the Swiss PICUs. The nine patients admitted to Swiss PICUs during the study period suffering from pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and constituting 14% (9/63) of all SARS-CoV-2 positive hospitalized patients in Swiss children's hospitals caused a higher workload [total Nine Equivalents of nursing Manpower use Score (NEMS) points, p = 0.0008] and were classified to higher workload categories (p < 0.0001) than regular PICU patients (n = 4,881) admitted in 2019. The comparison of the characteristics of the eight Swiss PICUs shows that they were confronted by different organizational issues arising from temporary regulations put in place by the federal council. These general regulations had different consequences for the eight individual PICUs due to the differences between the PICUs. In addition, the temporal relationship of these different regulations influenced the available PICU resources, dependent on the characteristics of the individual PICUs. As pandemic continues, reflecting and learning from experience is essential to reduce workload, optimize bed occupancy and manage resources in each individual PICU. In a small country as Switzerland, with a relatively decentralized health care local differences between PICUs are considerable and should be taken into account when making policy decisions.

Endothelial glycocalyx degradation in multisystem inflammatory syndrome in children related to COVID-19.

Multisystem inflammatory syndrome in children (MIS-C) represents a rare but severe complication of severe acute respiratory syndrome coronavirus 2 infection affecting children that can lead to myocardial injury and shock. Vascular endothelial dysfunction has been suggested to be a common complicating factor in patients with coronavirus disease 2019 (COVID-19). This study aims to characterize endothelial glycocalyx degradation in children admitted with MIS-C. We collected blood and urine samples and measured proinflammatory cytokines, myocardial injury markers, and endothelial glycocalyx markers in 17 children admitted with MIS-C, ten of which presented with inflammatory shock requiring intensive care admission and hemodynamic support with vasopressors. All MIS-C patients presented signs of glycocalyx deterioration with elevated levels of syndecan-1 in blood and both heparan sulfate and chondroitin sulfate in the urine. The degree of glycocalyx shedding correlated with tumor necrosis factor-α concentration. Five healthy age-matched children served as controls. Patients with MIS-C presented severe alteration of the endothelial glycocalyx that was associated with disease severity. Future studies should clarify if glycocalyx biomarkers could effectively be predictive indicators for the development of complications in adult patients with severe COVID-19 and children with MIS-C. KEY MESSAGES : Children admitted with MIS-C presented signs of endothelial glycocalyx injury with elevated syndecan-1 and heparan sulfate level. Syndecan-1 levels were associated with MIS-C severity and correlated TNF-α concentration. Syndecan-1 and heparan sulfate may represent potential biomarkers for patients with severe COVID-19 or MIS-C.