Abcc8 (sulfonylurea receptor-1) knockout mice exhibit reduced axonal injury, cytotoxic edema and cognitive dysfunction vs. wild-type in a cecal ligation and puncture model of sepsis.

Sepsis-associated brain injury (SABI) is characterized by an acute deterioration of mental status resulting in cognitive impairment and acquisition of new and persistent functional limitations in sepsis survivors. Previously, we reported that septic mice had evidence of axonal injury, robust microglial activation, and cytotoxic edema in the cerebral cortex, thalamus, and hippocampus in the absence of blood-brain barrier disruption. A key conceptual advance in the field was identification of sulfonylurea receptor 1 (SUR1), a member of the adenosine triphosphate (ATP)-binding cassette protein superfamily, that associates with the transient receptor potential melastatin 4 (TRPM4) cation channel to play a crucial role in cerebral edema development. Therefore, we hypothesized that knockout (KO) of Abcc8 (Sur1 gene) is associated with a decrease in microglial activation, cerebral edema, and improved neurobehavioral outcomes in a murine cecal ligation and puncture (CLP) model of sepsis. Sepsis was induced in 4-6-week-old Abcc8 KO and wild-type (WT) littermate control male mice by CLP. We used immunohistochemistry to define neuropathology and microglial activation along with parallel studies using magnetic resonance imaging, focusing on cerebral edema on days 1 and 4 after CLP. Abcc8 KO mice exhibited a decrease in axonal injury and cytotoxic edema vs. WT on day 1. Abcc8 KO mice also had decreased microglial activation in the cerebral cortex vs. WT. These findings were associated with improved spatial memory on days 7-8 after CLP. Our study challenges a key concept in sepsis and suggests that brain injury may not occur merely as an extension of systemic inflammation. We advance the field further and demonstrate that deletion of the SUR1 gene ameliorates CNS pathobiology in sepsis including edema, axonal injury, neuroinflammation, and behavioral deficits. Benefits conferred by Abcc8 KO in the murine CLP model warrant studies of pharmacological Abcc8 inhibition as a new potential therapeutic strategy for SABI.

Multidrug-resistant organisms: A significant cause of severe sepsis in pediatric intestinal and multi-visceral transplantation.

Severe sepsis in immunocompromised children is associated with increased mortality. This paper describes the epidemiology landscape, clinical acuity, and outcomes for severe sepsis in pediatric intestinal (ITx) and multi-visceral (MVTx) transplant recipients requiring admission to the pediatric intensive care unit (PICU). Severe sepsis episodes were retrospectively reviewed in 51 ITx and MVTx patients receiving organs between 2009 and 2015. Twenty-nine (56.8%) patients had at least one sepsis episode (total of 63 episodes) through December 2016. Bacterial etiologies accounted for 66.7% of all episodes (n = 42), occurring a median of 122.5 days following transplant (IQR 59-211.8 days). Multidrug-resistant organisms (MDROs) accounted for 73.8% of bacterial infections; extended spectrum beta-lactamase producers, vancomycin-resistant enterococcus, and highly-resistant Pseudomonas aeruginosa were the most commonly identified. Increased mechanical ventilation and vasoactive requirements were noted in MDRO episodes (OR 3.03, 95% CI 1.09-8.46 and OR 3.07, 95% CI 1.09-8.61, respectively; p < .05) compared to non-MDRO episodes. PICU length of stay was significantly increased for MDRO episodes (7 vs. 3 days, p = .02). Graft loss was 24.1% (n = 7) and mortality was 24.1% (n = 7) in patients who experienced severe sepsis. Further attention is needed for MDRO risk mitigation and modification of sepsis treatment guidelines to ensure MDRO coverage for this population.

Factors Associated With Neurobehavioral Complications in Pediatric Abdominal Organ Transplant Recipients Identified Using Computable Composite Definitions.

OBJECTIVES: Neurologic complications occur in up to 40% of adult abdominal solid organ transplant recipients and are associated with increased mortality. Comparable pediatric data are sparse. This study describes the occurrence of neurologic and behavioral complications (neurobehavioral complications) in pediatric abdominal solid organ transplant recipients. We examine the association of these complications with length of stay, mortality, and tacrolimus levels. DESIGN: The electronic health record was interrogated for inpatient readmissions of pediatric abdominal solid organ transplant recipients from 2009 to 2017. A computable composite definition of neurobehavioral complication, defined using structured electronic data for neurologic and/or behavioral phenotypes, was created. SETTING: Quaternary children's hospital with an active transplant program. PATIENTS: Pediatric abdominal solid organ transplant recipients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Computable phenotypes demonstrated a specificity 98.7% and sensitivity of 63.0% for identifying neurobehavioral complications. There were 1,542 readmissions among 318 patients, with 65 (20.4%) having at least one admission with a neurobehavioral complication (total 109 admissions). Median time from transplant to admission with neurobehavioral complication was 1.2 years (interquartile range, 0.52-2.28 yr). Compared to encounters without an identified neurobehavioral complication, encounters with a neurobehavioral complication were more likely to experience ICU admission (odds ratio, 3.9; 2.41-6.64; p < 0.001), have longer ICU length of stay (median 10.3 vs 2.2 d; p < 0.001) and hospital length of stay (8.9 vs 4.3 d; p < 0.001), and demonstrate higher maximum tacrolimus level (12.3 vs 9.8 ng/mL; p = 0.001). Patients with a neurobehavioral complication admission were more likely to die (odds ratio, 5.04; 1.49-17.09; p = 0.009). In a multivariable analysis, type of transplant, ICU admission, and tacrolimus levels were independently associated with the presence of a neurobehavioral complication. CONCLUSIONS: Common electronic health record variables can be used to accurately identify neurobehavioral complications in the pediatric abdominal solid organ transplant population. Late neurobehavioral complications are associated with increased hospital resource utilization, mortality, and tacrolimus exposure. Additional studies are required to delineate the relationship between maximum tacrolimus level and neurobehavioral complications to guide therapeutic drug monitoring and dosing.

Use of C-Reactive Protein and Ferritin Biomarkers in Daily Pediatric Practice.

Recent pediatric clinical research has begun to focus on risk stratification tools using multibiomarker models. C-reactive protein (CRP) and ferriti biomarkers are widely available and used to varying degrees in daily practice, but there is no single source examining the evidence behind their use.We set out to summarize the evidence behind the use of CRP and ferritin biomarkers in pediatric practice and to begin development of a consensus for their future use for pediatricians.All the literature involving CRP and ferritin in pediatrics available on PubMed was surveyed. Research applicable to daily pediatric practice was summarized in the body of the article. Pediatric clinicians of various subspecialties contributed to the summary of the use of CRP and ferritin biomarkers in clinical practice in various disease processes. A clinical decision pathway is described, and evidence is summarized.CRP and ferritin biomarkers have diverse uses with various cutoff values in the literature, making their use in daily practice difficult. Elevation of these markers coincides with their significant elevation in uncontrolled inflammation.CRP and ferritin biomarkers are widely used in pediatrics. This review provides a resource summarizing evidence into a single source. There is sufficient evidence to indicate that these biomarkers of inflammation can be useful in guiding clinical decision making in specific clinical scenarios; however, further work is needed to improve their use in clinical practice.

Therapeutic Plasma Exchange in Children With Thrombocytopenia-Associated Multiple Organ Failure: The Thrombocytopenia-Associated Multiple Organ Failure Network Prospective Experience.

OBJECTIVE: The objective was to compare the resolution of organ dysfunction, 28-day mortality, and biochemical markers in children with thrombocytopenia-associated multiple organ failure who received therapeutic plasma exchange versus no therapeutic plasma exchange. DESIGN: Observational longitudinal cohort study. SETTING: Nine U.S. PICUs. PATIENTS: Eighty-one children with sepsis-induced thrombocytopenia-associated multiple organ failure. INTERVENTIONS: Therapeutic plasma exchange. MEASUREMENTS AND MAIN RESULTS: Adjusted relative risk for 28-day mortality was modeled using standard multivariate regression with propensity score weighting to reduce covariate confounding. Change from baseline Pediatric Logistic Organ Dysfunction scores between therapeutic plasma exchange and no therapeutic plasma exchange differed in temporal pattern during the first week (p = 0.009). By day 4, mean Pediatric Logistic Organ Dysfunction score declined by 7.9 points (95% CI, -10.8 to -5.1) in the therapeutic plasma exchange-treated group compared with no change with no therapeutic plasma exchange. Use of therapeutic plasma exchange was associated with reduced 28-day mortality by multivariate analysis (adjusted relative risk, 0.45; 95% CI, 0.23-0.90; p = 0.02) and by propensity score weighting (adjusted relative risk, 0.46; 95% CI, 0.22-0.97; p = 0.04). CONCLUSIONS: Therapeutic plasma exchange use in thrombocytopenia-associated multiple organ failure was associated with a decrease in organ dysfunction. After accounting for several risk factors, 28-day all-cause mortality was lower in children treated with therapeutic plasma exchange compared with those receiving no therapeutic plasma exchange. A multicenter randomized clinical trial is necessary to determine a causal relationship.

Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms.

OBJECTIVES: To describe characteristics of liver transplant patients with severe sepsis in the PICU. DESIGN: Retrospective descriptive analysis. SETTING: Tertiary children's hospital PICU. PATIENTS: Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1-6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25-39.75 d) and 25 days (9-41 d), whereas 54.5 days (17-131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes. CONCLUSIONS: We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies.

Presenting predictors and temporal trends of treatment-related outcomes in diabetic ketoacidosis.

OBJECTIVE: This study examines temporal trends in treatment-related outcomes surrounding a diabetic ketoacidosis (DKA) performance improvement intervention consisting of mandated intensive care unit admission and implementation of a standardized management pathway, and identifies physical and biochemical characteristics associated with outcomes in this population. METHODS: A retrospective cohort of 1225 children with DKA were identified in the electronic health record by international classification of diseases codes and a minimum pH less than 7.3 during hospitalization at a quaternary children's hospital between April, 2009 and May, 2016. Multivariable regression examined predictors and trends of hypoglycemia, central venous line placement, severe hyperchloremia, head computed tomography (CT) utilization, treated cerebral edema and hospital length of stay (LOS). RESULTS: The incidence of severe hyperchloremia and head CT utilization decreased during the study period. Among patients with severe DKA (presenting pH < 7.1), the intervention was associated with decreasing LOS and less variability in LOS. Lower pH at presentation was independently associated with increased risk for all outcomes except hypoglycemia, which was associated with higher pH. Patients treated for cerebral edema had a lower presenting mean systolic blood pressure z score (0.58 [95% confidence interval (CI) -0.02-1.17] vs 1.23 [1.13-1.33]) and a higher maximum mean systolic blood pressure (SBP) z score during hospitalization (3.75 [3.19-4.31] vs 2.48 [2.38-2.58]) compared to patients not receiving cerebral edema treatment. Blood pressure and cerebral edema remained significantly associated after covariate adjustment. CONCLUSION: Treatment-related outcomes improved over the entire study period and following a performance improvement intervention. The association of SBP with cerebral edema warrants further study.

Brain-Specific Serum Biomarkers Predict Neurological Morbidity in Diagnostically Diverse Pediatric Intensive Care Unit Patients.

BACKGROUND: Unexpected neurological morbidity in Pediatric Intensive Care Units (PICUs) remains high and is difficult to detect proactively. Brain-specific biomarkers represent a novel approach for early detection of neurological injury. We sought to determine whether serum concentrations of neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, specific for neurons, oligodendrocytes, and glia, respectively, were predictive of neurological morbidity in critically ill children. METHODS: Serum was prospectively collected on days 1-7 from diagnostically diverse PICU patients (n = 103). Unfavorable neurological outcome at hospital discharge was defined as Pediatric Cerebral Performance Category (PCPC) score of 3-6 with a deterioration from baseline. NSE, MBP, and S100B concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Peak biomarker levels were greater in patients with unfavorable versus favorable neurological outcome [NSE 39.4 ± 44.1 vs. 12.2 ± 22.9 ng/ml (P = 0.005), MBP 9.1 ± 11.5 vs. 0.6 ± 1.3 ng/ml (P = 0.003), S100B 130 ± 232 vs. 34 ± 70 pg/ml (P = 0.04), respectively; mean ± SD]. Peak levels were each independently associated with unfavorable neurological outcome when controlling for presence of primary neurologic admission diagnosis and poor baseline PCPC using logistic regression analysis (NSE, P = 0.04; MBP, P = 0.004; S100B, P = 0.04), and had the following receiver operating characteristics: NSE 0.75 (0.58, 0.92), MBP 0.81 (0.66, 0.94), and S100B 0.80 (0.67, 0.93) (area under the curve [95% confidence intervals]). CONCLUSIONS: Prospectively collected brain-specific serum biomarkers predict unfavorable neurological outcome in critically ill children. Serum biomarkers used in conjunction with clinical data could be used to generate models predicting early detection of neurological injury, allowing for more timely diagnostic and therapeutic interventions, potentially reducing neurological morbidity in the PICU.

Dietary Supplementation With Nonfermentable Fiber Alters the Gut Microbiota and Confers Protection in Murine Models of Sepsis.

OBJECTIVES: Links between microbial alterations and systemic inflammation have been demonstrated in chronic disease, but little is known about these interactions during acute inflammation. This study investigates the effect of dietary supplementation with cellulose, a nonfermentable fiber, on the gut microbiota, inflammatory markers, and survival in two murine models of sepsis. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: Six-week-old male C57BL/6 wild-type mice. INTERVENTIONS: Mice were assigned to low-fiber, normal-fiber, or high-fiber diets with or without antibiotics for 2 weeks and then subjected to sepsis by cecal ligation and puncture or endotoxin injection. Fecal samples were collected for microbiota analyses before and after dietary interventions. MEASUREMENTS AND MAIN RESULTS: Mice that received a high-fiber diet demonstrated increased survival after cecal ligation and puncture relative to mice receiving low-fiber or normal-fiber diets. The survival benefit was associated with decreased serum concentration of pro-inflammatory cytokines, reduced neutrophil infiltration in the lungs, and diminished hepatic inflammation. The high-fiber diet also increased survival after endotoxin injection. Bacterial 16S ribosomal RNA gene sequences from each sample were amplified, sequenced, and analyzed. Fiber supplementation yielded an increase in relative abundance of the genera Akkermansia and Lachnospiraceae, taxa commonly associated with metabolic health. Administration of antibiotics to mice on the high-fiber diet negated the enrichment of Akkermansia species and the survival benefit after cecal ligation and puncture. CONCLUSION: Dietary supplementation with cellulose offers a microbe-mediated survival advantage in murine models of sepsis. Improved understanding of the link between diet, the microbiota, and systemic illness may yield new therapeutic strategies for patients with sepsis.

American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock.

OBJECTIVES: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine "Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock." DESIGN: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006-2014). The PubMed/Medline/Embase literature (2006-14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups. MEASUREMENTS AND MAIN RESULTS: The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations. CONCLUSIONS: The major new recommendation in the 2014 update is consideration of institution-specific use of 1) a "recognition bundle" containing a trigger tool for rapid identification of patients with septic shock, 2) a "resuscitation and stabilization bundle" to help adherence to best practice principles, and 3) a "performance bundle" to identify and overcome perceived barriers to the pursuit of best practice principles.

Autophagy Biomarkers Beclin 1 and p62 are Increased in Cerebrospinal Fluid after Traumatic Brain Injury.

BACKGROUND: Autophagy is a process that recycles damaged proteins and organelles. Beclin 1 is involved in the nucleation phase, while p62 is consumed during the elongation phase. We hypothesized that these autophagy biomarkers are increased in cerebrospinal fluid (CSF) after traumatic brain injury (TBI) in children and associated with unfavorable outcome. METHODS: Thirty children with severe TBI had CSF collected on days 1, 3, and 7. Patients without TBI or meningoencephalitis served as controls. Beclin 1 and p62 were measured by ELISA. Outcome was assigned 6 months after injury (Glasgow Outcome Scale score; GOS). RESULTS: Mean and peak CSF beclin 1 and p62 levels were increased compared to controls (P < 0.05). Peak p62 levels were higher in patients with unfavorable versus favorable outcome (0.79 ± 1.03 vs. 0.17 ± 0.54 ng/ml, respectively; mean ± SD, P = 0.002) and were independently associated with outcome when controlling for age and initial Glasgow Coma Scale score (P = 0.019; AUC 0.88, 95% CI 0.76, 1.00). CONCLUSIONS: Beclin 1 and p62 are increased in CSF after TBI, suggesting increased autophagy with impairment of, and/or exceeding the capacity for, autophagic flux. The association of increased p62 with unfavorable outcome suggests that autophagy in excess of the capacity to clear degradation products may be deleterious after TBI.

Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing rat brain and in primary cortical neurons in vitro.

Increased autophagy/mitophagy is thought to contribute to cerebellar dysfunction in Purkinje cell degeneration mice. Intriguingly, cerebellar Purkinje cells are highly vulnerable to hypoxia-ischemia (HI), related at least in part to their high metabolic activity. Whether or not excessive or supraphysiologic autophagy plays a role in Purkinje cell susceptibility to HI is unknown. Accordingly, we evaluated the role of autophagy in the cerebellum after global ischemia produced by asphyxial cardiac arrest in postnatal day (PND) 16-18 rats, using siRNA-targeted inhibition of Atg7, necessary for microtubule-associated protein light chain 3-II (LC3-II) and Atg12-Atg5 complex formation. Two days before a 9min asphyxial cardiac arrest or sham surgery, Atg7 or control siRNA was injected intracisternally to target the cerebellum. Treatment with Atg7 siRNA: 1) reduced Atg7 protein expression in the cerebellum by 56%; 2) prevented the typical ischemia-induced formation of LC3-II in the cerebellum 24h after asphyxial cardiac arrest; 3) improved performance on the beam-balance apparatus on days 1-5; and 4) increased calbindin-labeled Purkinje cell survival assessed on day 14. Improved Purkinje cell survival was more consistent in female vs. male rats, and improved beam-balance performance was only seen in female rats. Similar responses to Atg7 siRNA i.e. reduced autophagy and neurodegeneration vs. control siRNA were seen when exposing sex-segregated green fluorescent protein-LC3 tagged mouse primary cortical neurons to oxygen glucose deprivation in vitro. Thus, inhibition of autophagy after global ischemia in PND 16-18 rats leads to increased survival of Purkinje cells and improved motor performance in a sex-dependent manner.

Poly(ADP-ribose) polymerase 1-sirtuin 1 functional interplay regulates LPS-mediated high mobility group box 1 secretion.

Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP-ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD(+)) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD(+)-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis.

Cerebrospinal Fluid Markers of Macrophage and Lymphocyte Activation After Traumatic Brain Injury in Children.

OBJECTIVES: The magnitude and role of the cellular immune response following pediatric traumatic brain injury remains unknown. We tested the hypothesis that macrophage/microglia and T-cell activation occurs following pediatric traumatic brain injury by measuring cerebrospinal fluid levels of soluble cluster of differentiation 163 and ferritin and soluble interleukin-2 receptor α, respectively, and determined whether these biomarkers were associated with relevant clinical variables and outcome. DESIGN: Retrospective analysis of samples from an established, single-center cerebrospinal fluid bank. SETTING: PICU in a tertiary children's hospital. PATIENTS: Sixty-six pediatric patients after severe traumatic brain injury (Glasgow Coma Scale score < 8) who were 1 month to 16 years old and 17 control patients who were 1 month to 14 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cerebrospinal fluid levels of soluble cluster of differentiation 163, ferritin, and soluble interleukin-2 receptor α were determined by enzyme-linked immunosorbent assay at two time points (t1 = 17 ± 10 hr; t2 = 72 ± 15 hr) for each traumatic brain injury patient. Cerebrospinal fluid levels of soluble cluster of differentiation 163, ferritin, and soluble interleukin-2 receptor α after traumatic brain injury were compared with controls and analyzed for associations with age, patient sex, initial Glasgow Coma Scale score, diagnosis of abusive head trauma, the presence of hemorrhage on CT scan, and Glasgow Outcome Scale score. Cerebrospinal fluid level of soluble cluster of differentiation 163 was increased in traumatic brain injury patients at t2 versus t1 and controls (median, 95.4 ng/mL [interquartile range, 21.8-134.0 ng/mL] vs 31.0 ng/mL [5.7-77.7 ng/mL] and 27.8 ng/mL [19.1-43.1 ng/mL], respectively; p < 0.05). Cerebrospinal fluid level of ferritin was increased in traumatic brain injury patients at t2 and t1 versus controls (8.3 ng/mL [<7.5-19.8 ng/mL] and 8.9 ng/mL [<7.5-26.7 ng/mL] vs <7.5 ng/mL below lower limit of detection, respectively; p < 0.05). Cerebrospinal fluid levels of soluble interleukin-2 receptor α in traumatic brain injury patients at t2 and t1 were not different versus controls. Multivariate regression revealed associations between high ferritin and age 4 years or younger, lower Glasgow Coma Scale score, abusive head trauma, and unfavorable Glasgow Outcome Scale score. CONCLUSIONS: Children with traumatic brain injury demonstrate evidence for macrophage activation after traumatic brain injury, and in terms of cerebrospinal fluid ferritin, this appears more prominent with young age, initial injury severity, abusive head trauma, and unfavorable outcome. Further study is needed to determine whether biomarkers of macrophage activation may be used to discriminate between aberrant and adaptive immune responses and whether inflammation represents a therapeutic target after traumatic brain injury.

A Case Series of Persistent SARS-CoV-2 Infection in Immunocompromised Pediatric Patients.

Diagnosis and management of SARS-CoV-2 infection in immunocompromised patients are extremely challenging. These patients can have atypical clinical courses, and there is a paucity of data regarding clinical features, diagnostic findings, and the safety and efficacy of available therapeutic agents used to treat COVID-19 in these patients. In this case series, we report atypical COVID-19 presentations in 4 immunocompromised pediatric patients who were admitted with acute respiratory failure after an initial diagnosis of COVID-19 a few weeks earlier. All patients included in this cohort showed persistent worsening respiratory symptoms for several weeks before hospital presentation. While they manifested common COVID-19 sequelae, they also had rare COVID-19-related pathognomonic and radiographic features developed along their hospital course. Multiple therapeutic agents were used in their COVID-19 management, including corticosteroids, remdesivir, and monoclonal antibodies. All three patients who have received concurrent therapy with remdesivir, hydrocortisone, and monoclonal antibodies survived, and only one patient died as a direct complication of COVID-19 ARDS with secondary pulmonary mucormycosis. Our outcomes suggest the potential benefit of remdesivir use in combination with hydrocortisone and monoclonal antibodies in the management of severe COVID-19 ARDS in this group, as well as the importance of close surveillance and early administration of broad empirical antimicrobial and antifungal coverage if clinically indicated in this high-risk population.

Antibiotic therapy in neonatal and pediatric septic shock.

Severe sepsis accounts for nearly 4,500 deaths (mortality rate 10%), and is responsible for nearly $2 billion annual healthcare expenditure in the United States. Early and speedy treatment of critically ill septic patients can halt or reduce the likelihood of physiologic progression to multi-system organ failure. A cornerstone of this therapeutic strategy is antibiotic administration. In this review, we discuss the empirical treatment strategies for the treatment of early and late neonatal sepsis, along with pediatric sepsis. Furthermore, we discuss the rationale that underlies the adoption of such treatment strategies. The present article also discusses the emergence of multi-drug organisms as the causative agents for sepsis, i.e. methicillin-resistant Staphylococcus aureus (MRSA), resistant enterococci and Klebsiella pneumoniae carbapenemases (KPC).