Blood Purification with oXiris© in Critically Ill Children with Vasoplegic Shock.

INTRODUCTION: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. As such, circulating cytokines and danger- and pathogen-associated molecular patterns (such as endotoxins) are recognized as central in the pathogenesis of sepsis and organ dysfunction. Removing these compounds by extracorporeal blood filtration, commonly considered blood purification, may improve the septic patients' condition. This study aimed to assess the vaso-inotropic support evolution over time in pediatric patients with vasoplegic shock treated with oXiris©. METHODS: All patients aged below 18 years admitted at the Paris Saclay University Quaternary Pediatric Intensive Care Unit with vasoplegic shock and acute kidney injury and treated with oXiris© between October 2017 and January 2020 were included. The vaso-inotropic score and the 28-day mortality were assessed. Improvement under treatment was defined as a 50% decrease in the vaso-inotropic score following 24 h of oXiris© therapy. RESULTS: Eleven pediatric patients aged 2-15 years and weighing 11-60 kg were admitted with vasoplegic shock and acute kidney injury. They received thirteen sessions of oXiris© therapy for septic shock (N = 7) and liver failure (N = 6). Eight patients did not improve their condition during the session, and five ultimately died (37.5% survival). Five patients improved, decreasing their inotropic support by >50% in 24 h. Among them, four survived (80%). CONCLUSION: Hemofiltration and extracorporeal blood purification with oXiris© can be used in pediatric patients with vasoplegic shock with rapid improvement in hemodynamics in selected patients.

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Resident PW1+ Progenitor Cells Participate in Vascular Remodeling During Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension is characterized by vascular remodeling and neomuscularization. PW1(+) progenitor cells can differentiate into smooth muscle cells (SMCs) in vitro. OBJECTIVE: To determine the role of pulmonary PW1(+) progenitor cells in vascular remodeling characteristic of pulmonary arterial hypertension. METHODS AND RESULTS: We investigated their contribution during chronic hypoxia-induced vascular remodeling in Pw1(nLacZ+/-) mouse expressing ß-galactosidase in PW1(+) cells and in differentiated cells derived from PW1(+) cells. PW1(+) progenitor cells are present in the perivascular zone in rodent and human control lungs. Using progenitor markers, 3 distinct myogenic PW1(+) cell populations were isolated from the mouse lung of which 2 were significantly increased after 4 days of chronic hypoxia. The number of proliferating pulmonary PW1(+) cells and the proportion of ß-gal(+) vascular SMC were increased, indicating a recruitment of PW1(+) cells and their differentiation into vascular SMC during early chronic hypoxia-induced neomuscularization. CXCR4 inhibition using AMD3100 prevented PW1(+) cells differentiation into SMC but did not inhibit their proliferation. Bone marrow transplantation experiments showed that the newly formed ß-gal(+) SMC were not derived from circulating bone marrow-derived PW1(+) progenitor cells, confirming a resident origin of the recruited PW1(+) cells. The number of pulmonary PW1(+) cells was also increased in rats after monocrotaline injection. In lung from pulmonary arterial hypertension patients, PW1-expressing cells were observed in large numbers in remodeled vascular structures. CONCLUSIONS: These results demonstrate the existence of a novel population of resident SMC progenitor cells expressing PW1 and participating in pulmonary hypertension-associated vascular remodeling.

Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study.

BACKGROUND: De-regulated host response to severe coronavirus disease 2019 (COVID-19), directly referring to the concept of sepsis-associated immunological dysregulation, seems to be a strong signature of severe COVID-19. Myeloid cells phenotyping is well recognized to diagnose critical illness-induced immunodepression in sepsis and has not been well characterized in COVID-19. The aim of this study is to review phenotypic characteristics of myeloid cells and evaluate their relations with the occurrence of secondary infection and mortality in patients with COVID-19 admitted in an intensive care unit. METHODS: Retrospective analysis of the circulating myeloid cells phenotypes of adult COVID-19 critically ill patients. Phenotyping circulating immune cells was performed by flow cytometry daily for routine analysis and twice weekly for lymphocytes and monocytes subpopulations analysis, as well as monocyte human leukocyte antigen (mHLA)-DR expression. RESULTS: Out of the 29 critically ill adult patients with severe COVID-19 analyzed, 12 (41.4%) developed secondary infection and six patients died during their stay. Monocyte HLA-DR kinetics was significantly different between patients developing secondary infection and those without, respectively, at day 5-7 and 8-10 following admission. The monocytes myeloid-derived suppressor cells to total monocytes ratio was associated with 28- and 60-day mortality. Those myeloid characteristics suggest three phenotypes: hyperactivated monocyte/macrophage is significantly associated with mortality, whereas persistent immunodepression is associated with secondary infection occurrence compared to transient immunodepression. CONCLUSIONS: Myeloid phenotypes of critically ill COVID-19 patients may be associated with development of secondary infection, 28- and 60-day mortality.

pCLIF-SOFA is a reliable outcome prognostication score of critically ill children with cirrhosis: an ESPNIC multicentre study.

BACKGROUND AND AIMS: Data on outcome of critically ill children with cirrhosis are scarce. We aimed to evaluate the prognostic accuracy of sequential organs scoring systems in children with cirrhosis admitted to Paediatric Intensive Care Units (PICU). METHODS: We performed a multicentre retrospective analysis of children with cirrhosis admitted into four European PICUs between 2011 and 2016. Investigators were members of the ESPNIC liver failure and support working group. Paediatric End-Stage Liver Disease (PELD) and paediatric chronic liver failure sequential organ failure assessment score (pCLIF-SOFA) diagnostic accuracy for 28- and 60-day liver transplantation, 28-day mortality and 60-day composite outcome (ie. death or liver transplantation) were tested. RESULTS: One-hundred-and-thirty children were included. The main causes for PICU admission were acute-on-chronic liver failure (ACLF), gastrointestinal bleeding and sepsis. Twenty-nine percent died and 22.3% were transplanted by day-60 after PICU admission. On multivariable analysis, pCLIF-SOFA was the only predictor of mortality at day-28 and of composite outcome. Both pCLIF-SOFA and ACLF were independently associated with emergent liver transplantation. The pCLIF-SOFA score higher than 9 well predicted a 28-day mortality with a sensitivity of 87.8% and a specificity of 77.3%. A pCLIF-SOFA score higher than 7 was independently associated with liver transplantation on day-60. Stage 3 AKI assessed with KDIGO classification was significantly associated with 28-day mortality. CONCLUSIONS: Half of critically ill cirrhotic children admitted to PICU either died or were transplanted within the initial 28-day period. On admission pCLIF-SOFA score accurately identify patients transplanted at day-28 and day-60 to those alive without LT and is associated with 28-day mortality and composite outcome at day-60.

Infective Endocarditis Risk After Percutaneous Pulmonary Valve Implantation With the Melody and Sapien Valves.

OBJECTIVES: This study compared the risk of infective endocarditis (IE) after percutaneous pulmonary valve implantation (PPVI) with the Sapien and Melody valves. BACKGROUND: The incidence of IE after PPVI is estimated at 3% per year with the Melody valve. The Sapien valve is a more recently marketed valve used for PPVI. METHODS: We retrospectively included consecutive patients who underwent PPVI at a single center between 2008 and 2016. IE was diagnosed using the modified DUKE criteria. RESULTS: PPVI was performed in 79 patients (Melody valve, 40.5%; Sapien valve, 59.5%). Median age was 24.9 years (range 18.1 to 34.6). IE occurred in 8 patients (10.1%) at a median of 1.8 years (minimum: 1.0; maximum: 5.6) after surgery. Causative organisms were methicillin-sensitive Staphylococcus aureus (n = 3), Staphylococcus epidermidis (n = 1), Streptococcus mitis (n = 1), Aerococcus viridans (n = 1), Corynebacterium striatum (n = 1), and Haemophilus influenzae (n = 1). All 8 cases occurred after Melody PPVI (25.0% vs. 0.0%). The incidence of IE was 5.7% (95% confidence interval: 2.9% to 11.4%) per person-year after Melody PPVI. The Kaplan-Meier cumulative incidence of IE with Melody PPVI was 24.0% (95% confidence interval: 12.2% to 43.9%) after 4 years and 30.1% (95% confidence interval: 15.8% to 52.5%) after 6 years, compared with 0.0% with the Sapien PPVI after 4 years (p < 0.04 by log-rank test). There was a trend toward a higher incidence of IE in the first 20 patients with Melody PPVI (who received prophylactic antibiotics during the procedure only) and in patients who had percutaneous interventions, dental care, or noncardiac surgery after PPVI. CONCLUSIONS: IE after PPVI may be less common with the Sapien compared with the Melody valve.

Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension.

UNLABELLED: The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10(11) DRP/animal) as compared to AAV1. CONTROL: The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.