Hundreds of antimicrobial peptides create a selective barrier for insect gut symbionts.

The spatial organization of gut microbiota is crucial for the functioning of the gut ecosystem, although the mechanisms that organize gut bacterial communities in microhabitats are only partially understood. The gut of the insect Riptortus pedestris has a characteristic microbiota biogeography with a multispecies community in the anterior midgut and a monospecific bacterial population in the posterior midgut. We show that the posterior midgut region produces massively hundreds of specific antimicrobial peptides (AMPs), the Crypt-specific Cysteine-Rich peptides (CCRs) that have membrane-damaging antimicrobial activity against diverse bacteria but posterior midgut symbionts have elevated resistance. We determined by transposon-sequencing the genetic repertoire in the symbiont Caballeronia insecticola to manage CCR stress, identifying different independent pathways, including AMP-resistance pathways unrelated to known membrane homeostasis functions as well as cell envelope functions. Mutants in the corresponding genes have reduced capacity to colonize the posterior midgut, demonstrating that CCRs create a selective barrier and resistance is crucial in gut symbionts. Moreover, once established in the gut, the bacteria differentiate into a CCR-sensitive state, suggesting a second function of the CCR peptide arsenal in protecting the gut epithelia or mediating metabolic exchanges between the host and the gut symbionts. Our study highlights the evolution of an extreme diverse AMP family that likely contributes to establish and control the gut microbiota.

Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants.

BACKGROUND: The safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)-associated lower respiratory tract infection when administered in healthy infants are unclear. METHODS: In a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen. RESULTS: A total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P = 0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P = 0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P = 0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group. CONCLUSIONS: Nirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510).

Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. We analyzed the B cell compartment in human newborns and identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis.

Surviving Sepsis Campaign Research Priorities 2023.

OBJECTIVES: To identify research priorities in the management, epidemiology, outcome, and pathophysiology of sepsis and septic shock. DESIGN: Shortly after publication of the most recent Surviving Sepsis Campaign Guidelines, the Surviving Sepsis Research Committee, a multiprofessional group of 16 international experts representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine, convened virtually and iteratively developed the article and recommendations, which represents an update from the 2018 Surviving Sepsis Campaign Research Priorities. METHODS: Each task force member submitted five research questions on any sepsis-related subject. Committee members then independently ranked their top three priorities from the list generated. The highest rated clinical and basic science questions were developed into the current article. RESULTS: A total of 81 questions were submitted. After merging similar questions, there were 34 clinical and ten basic science research questions submitted for voting. The five top clinical priorities were as follows: 1) what is the best strategy for screening and identification of patients with sepsis, and can predictive modeling assist in real-time recognition of sepsis? 2) what causes organ injury and dysfunction in sepsis, how should it be defined, and how can it be detected? 3) how should fluid resuscitation be individualized initially and beyond? 4) what is the best vasopressor approach for treating the different phases of septic shock? and 5) can a personalized/precision medicine approach identify optimal therapies to improve patient outcomes? The five top basic science priorities were as follows: 1) How can we improve animal models so that they more closely resemble sepsis in humans? 2) What outcome variables maximize correlations between human sepsis and animal models and are therefore most appropriate to use in both? 3) How does sepsis affect the brain, and how do sepsis-induced brain alterations contribute to organ dysfunction? How does sepsis affect interactions between neural, endocrine, and immune systems? 4) How does the microbiome affect sepsis pathobiology? 5) How do genetics and epigenetics influence the development of sepsis, the course of sepsis and the response to treatments for sepsis? CONCLUSIONS: Knowledge advances in multiple clinical domains have been incorporated in progressive iterations of the Surviving Sepsis Campaign guidelines, allowing for evidence-based recommendations for short- and long-term management of sepsis. However, the strength of existing evidence is modest with significant knowledge gaps and mortality from sepsis remains high. The priorities identified represent a roadmap for research in sepsis and septic shock.

Biological impact of manual blood exchange in malignant Bordetella pertussis infection in infants.

BACKGROUND AND OBJECTIVES: Manual blood exchange (MBE) is a leukoreduction therapy for hyperleukocytosis in Bordetella spp. INFECTION: We describe the impact of BE on clinical and biological parameters in critically ill children with malignant pertussis. MATERIALS AND METHODS: This is a monocentric retrospective review of patients with malignant pertussis infection treated with MBE. It describes the evolution of haemodynamic, ventilatory, haematologic and metabolic characteristics before and after MBE. RESULTS: Between January 2006 and December 2021, nine patients (median age 43 days, range: 13-80 days) had 16 MBE for malignant pertussis. All patients were mechanically ventilated, and 7/9 patients developed pulmonary hypertension during their paediatric intensive care unit (PICU) stay. Overall, 3/9 patients survived, and the mean PICU length of stay was 8.5 days (range: 1-52 days). We found a significant reduction of the leukocyte count (pre-MBE: 61.8 G/L [interquartile range (IQR): 55.8-74.8] vs. post-MBE: 19.4 G/L [IQR: 17.7-24.1]; p ≤ 0.001) and significant oxygenation improvement (pre-MBE SpO2/FiO2: 190 [IQR: 106-200] vs. post-MBE SpO2/FiO2: 242 [IQR: 149-250]; p = 0.03). The main side effects were a significant reduction of thrombocytes (pre-MBE: 411 G/L [IQR: 166.5-563.5] vs. post-MBE: 66 G/L [IQR: 46-82.5]; p = <0.001) and of ionized calcium (iCa) (pre-MBE iCa: 1.3 [IQR: 1.22-1.37] vs. post-MBE iCa: 1.25 [IQR: 1.85-2.24]; p = 0.03). CONCLUSION: MBE efficiently reduces leukocytes and improves oxygenation in severe Bordetella pertussis infection in infants. Careful monitoring of calcium and thrombocytes seems mandatory.

Neonatal hemodynamics of recipient twins after fetoscopic selective laser coagulation for twin-to-twin transfusion syndrome: An unicist classification.

To characterize the neonatal hemodynamic profiles in recipients born after twin-to-twin transfusion syndrome (TTTS) treated with fetoscopic selective laser coagulation (FSLC). Retrospective analysis during the first month of life of recipient twins. Of the 480 newborns born during an 11-year period, 138 recipient twins with prenatal FSLC were classified into four groups: no hemodynamic impairment (NoHI, n = 102, 74%), isolated high blood pressure (HighBP, n = 18, 13%), right ventricular outflow tract obstruction (RVOTO, n = 10, 7%), and cardiac failure (CF, n = 8, 6%). The time (median (IQR)) between FSLC and birth was significantly shorter in the HighBP (36 days (23-54)) and CF (44 days (18-54)) groups than in the RVOTO (91 days (68-112)) and NoHi (82 days (62-104)) groups (p < 0.001).     Conclusion: Four distinct and well-characterized groups of recipients were identified based on their hemodynamics. High blood pressure and heart failure occurred in approximately 20% of the infants and were associated with a time between laser coagulation and birth of less than 2 months. What is Known: • Twin-to-twin transfusion syndrome (TTTS) is characterized by a hemodynamic imbalance that leads to high fetal and neonatal mortality if left untreated. One-third of recipient twins born without prenatal fetoscopic laser coagulation (FSLC) develop a life-threatening cardiac failure. What is New: • Four distinct groups of recipient twins with prenatal FSLC have been identified based on their hemodynamics. High blood pressure and cardiac failure occurred in 20% of the infants and were associated with an interval between FSLC and birth of less than 2 months.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

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.

Criteria for Pediatric Sepsis-A Systematic Review and Meta-Analysis by the Pediatric Sepsis Definition Taskforce.

OBJECTIVE: To determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020. STUDY SELECTION: Case-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms "sepsis," "septicemia," or "septic shock" in the title or abstract. DATA EXTRACTION: Study characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed. DATA SYNTHESIS: One hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001). CONCLUSIONS: Strong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

Transcranial Doppler Ultrasonography in Children With Acute Liver Failure and Severe Hepatic Encephalopathy.

OBJECTIVES: To report our single-center use of transcranial Doppler (TCD) for noninvasive neuromonitoring in pediatric patients with acute liver failure (ALF). DESIGN: Retrospective cohort from January 2016 to June 2019. SETTING: PICU in Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), a national referral center for pediatric liver transplantation. PATIENTS: Pediatric patients with severe ALF (prothrombin time < 30% and Hepatic Encephalopathy score ≥ 3), on continuous venovenous high-flow hemofiltration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ten children were identified, six were transplanted (1/6 died) and four were not (3/4 died). TCD was performed several times per patient and the evolution of cerebral perfusion parameters was followed. Of interest, zero of six patients who survived lost end-diastolic velocity (EDV), whereas four of four patients who died did (difference, 100%; 95% CI, 37-100%; χ 2 , 9; degrees of freedom, 1; p = 0.0027). We failed to identify an association between pulsatility index (PI) or EDV, and severity of hepatic encephalopathy. CONCLUSIONS: TCD was a noninvasive and bedside available tool to detect and screen for presence of abnormal cerebral flow in children with ALF, according to age-related reference values. TCD detected reduced EDV and elevated PI in children with ALF awaiting transplant who died compared with those who survived.

Epidemiology of Neonatal Acute Respiratory Distress Syndrome: Prospective, Multicenter, International Cohort Study.

OBJECTIVES: Age-specific definitions for acute respiratory distress syndrome (ARDS) are available, including a specific definition for neonates (the "Montreux definition"). The epidemiology of neonatal ARDS is unknown. The objective of this study was to describe the epidemiology, clinical course, treatment, and outcomes of neonatal ARDS. DESIGN: Prospective, international, observational, cohort study. SETTING: Fifteen academic neonatal ICUs. PATIENTS: Consecutive sample of neonates of any gestational age admitted to participating sites who met the neonatal ARDS Montreux definition criteria. MEASUREMENTS AND MAIN RESULTS: Neonatal ARDS was classified as direct or indirect, infectious or noninfectious, and perinatal (≤ 72 hr after birth) or late in onset. Primary outcomes were: 1) survival at 30 days from diagnosis, 2) inhospital survival, and 3) extracorporeal membrane oxygenation (ECMO)-free survival at 30 days from diagnosis. Secondary outcomes included respiratory complications and common neonatal extrapulmonary morbidities. A total of 239 neonates met criteria for the diagnosis of neonatal ARDS. The median prevalence was 1.5% of neonatal ICU admissions with male/female ratio of 1.5. Respiratory treatments were similar across gestational ages. Direct neonatal ARDS (51.5% of neonates) was more common in term neonates and the perinatal period. Indirect neonatal ARDS was often triggered by an infection and was more common in preterm neonates. Thirty-day, inhospital, and 30-day ECMO-free survival were 83.3%, 76.2%, and 79.5%, respectively. Direct neonatal ARDS was associated with better survival outcomes than indirect neonatal ARDS. Direct and noninfectious neonatal ARDS were associated with the poorest respiratory outcomes at 36 and 40 weeks' postmenstrual age. Gestational age was not associated with any primary outcome on multivariate analyses. CONCLUSIONS: Prevalence and survival of neonatal ARDS are similar to those of pediatric ARDS. The neonatal ARDS subtypes used in the current definition may be associated with distinct clinical outcomes and a different distribution for term and preterm neonates.

Pediatric Acute Alcohol Intoxication Admitted to the ICU: A Review of 102 Cases in France.

OBJECTIVES: To describe the profile and clinical outcomes of children (<18 yr) admitted to intensive care for acute alcohol intoxication, with special attention to complications and to the subgroup that required intubation. DESIGN: Retrospective observational study. SETTING: Seven pediatric and three adult ICUs in France. PATIENTS: Children 1-17 yr admitted to intensive care for acute alcohol intoxication between January 1, 2010, and December 30, 2017. INTERVENTIONS: The study was observational and patients received standard care. MEASUREMENTS AND MAIN RESULTS: We included 102 patients, with 71 males (69.6%) and 31 females (30.4%). Mean age was not different between males and females (14.0 ± 3.0 yr [range, 2-17 yr] and 14.2 ± 1.3 yr [range, 11-17 yr]; p = 0.67); six children were younger than 10 years. Mean blood alcohol concentration was not significantly different in males and females (2.42 ± 0.86 and 2.20 ± 0.54 g/L, respectively; p = 0.51). Of the 102 patients, 58 (57%) required intubation. Factors significantly associated with requiring intubation were lower Glasgow Coma Scale score (p = 0.002), lower body temperature (p = 0.045), and higher blood alcohol concentration (p = 0.012); vascular filling, and electrolyte disturbances were not associated with needing intubation. Mean intubation time was 9.7 ± 5.2 hours. Among the 59 patients with Glasgow Coma Scale score less than 8, 12 did not require intubation. The most common metabolic disturbance was a high lactate level (48%), followed by hypokalemia (27.4%); 59 (58.2%) patients had hyperglycemia and three had hypoglycemia. CONCLUSIONS: Male adolescents make up the majority of pediatric patients admitted to intensive care for acute alcohol intoxication. A need for intubation was associated with a worse Glasgow Coma Scale, lower body temperature, and higher blood alcohol concentration. Intubation was usually required for less than 12 hours. Other acute medical complications reported in adults with acute alcohol intoxication, such as electrolyte disturbances and aspiration pneumonia, were rare in our pediatric patients.

The Surviving Sepsis Campaign: Research Priorities for Coronavirus Disease 2019 in Critical Illness.

OBJECTIVES: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. DESIGN: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. METHODS: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. RESULTS: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? CONCLUSIONS: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019.

European consensus recommendations for neonatal and paediatric retrievals of positive or suspected COVID-19 patients.

BACKGROUND: The 2020 novel coronavirus (SARS-Cov-2) pandemic necessitates tailored recommendations addressing specific procedures for neonatal and paediatric transport of suspected or positive COVID-19 patients. The aim of this consensus statement is to define guidelines for safe clinical care for children needing inter-facility transport while making sure that the clinical teams involved are sufficiently protected from SARS-CoV-2. METHODS: A taskforce, composed of members of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Transport section and the European Society for Paediatric Research (ESPR), reviewed the published literature and used a rapid, two-step modified Delphi process to formulate recommendations regarding safety and clinical management during transport of COVID-19 patients. RESULTS: The joint taskforce consisted of a panel of 12 experts who reached an agreement on a set of 17 recommendations specifying pertinent aspects on neonatal and paediatric COVID-19 patient transport. These included: case definition, personal protective equipment, airway management, equipment and strategies for invasive and non-invasive ventilation, special considerations for incubator and open stretcher transports, parents on transport and decontamination of transport vehicles. CONCLUSIONS: Our consensus recommendations aim to define current best-practice and should help guide transport teams dealing with infants and children with COVID-19 to work safely and effectively. IMPACT: We present European consensus recommendations on pertinent measures for transporting infants and children in times of the coronavirus (SARS-Cov-2 /COVID-19) pandemic. A panel of experts reviewed the evidence around transporting infants and children with proven or suspected COVID-19. Specific guidance on aspects of personal protective equipment, airway management and considerations for incubator and open stretcher transports is presented. Based on scant evidence, best-practice recommendations for neonatal and paediatric transport teams are presented, aiming for the protection of teams and patients. We highlight gaps in knowledge and areas of future research.

Surfactant therapies for pediatric and neonatal ARDS: ESPNIC expert consensus opinion for future research steps.

Pediatric (PARDS) and neonatal (NARDS) acute respiratory distress syndrome have different age-specific characteristics and definitions. Trials on surfactant for ARDS in children and neonates have been performed well before the PARDS and NARDS definitions and yielded conflicting results. This is mainly due to heterogeneity in study design reflecting historic lack of pathobiology knowledge. We reviewed the available clinical and preclinical data to create an expert consensus aiming to inform future research steps and advance the knowledge in this area. Eight trials investigated the use of surfactant for ARDS in children and ten in neonates, respectively. There were improvements in oxygenation (7/8 trials in children, 7/10 in neonates) and mortality (3/8 trials in children, 1/10 in neonates) improved. Trials were heterogeneous for patients' characteristics, surfactant type and administration strategy. Key pathobiological concepts were missed in study design. Consensus with strong agreement was reached on four statements: 1. There are sufficient preclinical and clinical data to support targeted research on surfactant therapies for PARDS and NARDS. Studies should be performed according to the currently available definitions and considering recent pathobiology knowledge. 2. PARDS and NARDS should be considered as syndromes and should be pre-clinically studied according to key characteristics, such as direct or indirect (primary or secondary) nature, clinical severity, infectious or non-infectious origin or patients' age. 3. Explanatory should be preferred over pragmatic design for future trials on PARDS and NARDS. 4. Different clinical outcomes need to be chosen for PARDS and NARDS, according to the trial phase and design, trigger type, severity class and/or surfactant treatment policy. We advocate for further well-designed preclinical and clinical studies to investigate the use of surfactant for PARDS and NARDS following these principles.

Lung transplantation in neonates and infants: ESPNIC survey of European neonatologists and pediatric intensivists.

Lung and heart & lung transplantations in neonates and infants are extreme treatments offered for some life-threatening conditions especially in some North-American centers with promising results. These transplantations are rarely performed in Europe, and we set up a continent-based survey to describe the attitude of European neonatologists and pediatric intensivists on the subject and identify the main indications for this transplantation and the obstacles for the realization of a European lung transplantation program.Conclusion: The main indications for lung transplantation program for neonates and infants are represented by congenital disorders, and physicians indicate as main obstacles the donors' availability. European neonatologists and pediatric intensivists are interested to create a European network to overcome this problem and realize a lung transplantation program for neonates and infants. What is Known: • Lung transplantation in neonates and infants seems to slowly increase, and some North-American centers accumulated a relevant experience. What is New: • European neonatologists and pediatric intensivists are interested in creating a European network for a lung transplantation program for neonates and infants. • The main indications for lung transplantation program for neonates and infants are represented by congenital disorders and main obstacle to lung transplantation is the donors' availability.

Mortality and Neurologic Sequelae in Influenza-Associated Encephalopathy: Retrospective Multicenter PICU Cohort in France.

OBJECTIVES: To describe and estimate the mortality rate of severe influenza-associated encephalopathy/encephalitis among children admitted to PICUs. DESIGN: Multicenter retrospective study. SETTING: Twelve French PICUs. PATIENTS: All children admitted for influenza-associated encephalopathy/encephalitis between 2010 and 2018 with no severe preexisting chronic neurologic disorders and no coinfection potentially responsible for the disease. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We collected the clinical presentation; laboratory, electroencephalographic, and MRI findings; and treatments used in the PICU. The primary outcome was mortality. The secondary outcomes included sequelae at discharge and last follow-up. We included 41 patients with a median (interquartile range) age of 4.7 years (2.5-8.2 yr). The main reasons for admission were altered consciousness (59%) and status epilepticus (34%); 48% of patients had meningitis, and one third had acute necrotizing encephalopathy on MRI. Mechanical ventilation was required in 73% of patients and hemodynamic support in 24%. The use of specific treatments was variable; steroids were given to 49% of patients. Seven patients (17%) died in the PICU. Median (interquartile range) PICU stay length was 7 days (2-13 d), and total hospital length of stay was 23 days (7-33 d). On hospital discharge, 49% (n = 20) had neurologic sequelae, with 27% (n = 11) having severe disabilities defined by modified Rankin Score greater than or equal to 4. CONCLUSIONS: Children requiring PICU admission for influenza-associated encephalopathy/encephalitis have high mortality and morbidity rates. The management remains highly variable due to the lack of guidelines.

Caring for Critically Ill Children With Suspected or Proven Coronavirus Disease 2019 Infection: Recommendations by the Scientific Sections' Collaborative of the European Society of Pediatric and Neonatal Intensive Care.

OBJECTIVES: In children, coronavirus disease 2019 is usually mild but can develop severe hypoxemic failure or a severe multisystem inflammatory syndrome, the latter considered to be a postinfectious syndrome, with cardiac involvement alone or together with a toxic shock like-presentation. Given the novelty of severe acute respiratory syndrome coronavirus 2, the causative agent of the recent coronavirus disease 2019 pandemic, little is known about the pathophysiology and phenotypic expressions of this new infectious disease nor the optimal treatment approach. STUDY SELECTION: From inception to July 10, 2020, repeated PubMed and open Web searches have been done by the scientific section collaborative group members of the European Society of Pediatric and Neonatal Intensive Care. DATA EXTRACTION: There is little in the way of clinical research in children affected by coronavirus disease 2019, apart from descriptive data and epidemiology. DATA SYNTHESIS: Even though basic treatment and organ support considerations seem not to differ much from other critical illness, such as pediatric septic shock and multiple organ failure, seen in PICUs, some specific issues must be considered when caring for children with severe coronavirus disease 2019 disease. CONCLUSIONS: In this clinical guidance article, we review the current clinical knowledge of coronavirus disease 2019 disease in critically ill children and discuss some specific treatment concepts based mainly on expert opinion based on limited experience and the lack of any completed controlled trials in children at this time.

Management and Outcomes of Neonatal Arteriovenous Brain Malformations with Cardiac Failure: A 17 Years' Experience in a Tertiary Referral Center.

OBJECTIVES: To assess the management and outcomes of neonatal arteriovenous brain malformations (mostly vein of Galen malformations) complicated by cardiac failure in the era of prenatal diagnosis and endovascular treatment in a tertiary referral center. STUDY DESIGN: This observational study included 77 living newborn infants with arteriovenous brain malformations with cardiac failure, admitted to our referral center from 2001 to 2017. All infants underwent cardiovascular evaluation including echocardiogram and brain magnetic resonance imaging. Long-term survivors had standard neurocognitive assessments. RESULTS: Infants were admitted to the neonatal intensive care unit at a median of 5 days of age (including 18 inborn patients since 2009). Sixty transarterial shunt embolizations were performed in 46 patients during their first month (at a median age of 7.5 days) or postponed beyond the first month in another 10 long-term survivors. Embolization was not performed in 21 infants, including 19 nonsurvivors with severe brain injury, uncontrolled cardiac failure, or multiple organ failure. Cardiac failure requiring vasopressor infusion occurred in 48 patients (64%) during the hospitalization. Infants who survived the first month underwent a median of 3 embolization sessions. Among the 51 survivors, 21 had a good outcome and 19 had a poor outcome at follow-up (median age, 5.3 years); 11 children were lost to follow-up. CONCLUSIONS: In the era of multidisciplinary prenatal diagnosis, using a standardized care protocol, 47% of liveborn infants with an arteriovenous shunt malformation with cardiac failure experienced a favorable outcome.