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BackgroundSevere critical illness-induced immune suppression, termed immunoparalysis, is associated with longer duration of organ dysfunction in septic children. mRNA studies have suggested differential benefit of hydrocortisone in septic children based on their immune phenotype, but this has not been shown using a functional readout of the immune response. This study represents a secondary analysis of a prospectively conducted immunophenotyping study of pediatric severe sepsis to test the hypothesis that hydrocortisone will be differentially associated with clinical outcomes in children with or without immunoparalysis.MethodsChildren with severe sepsis/septic shock underwent blood sampling within 48 h of sepsis onset. Immune function was measured by quantifying whole blood ex vivo LPS-induced TNFα production capacity, with a TNFα response ResultsOne hundred two children were enrolled (age 75 [6–160] months, 60% male). Thirty-one subjects received hydrocortisone and were more likely to be older (106 [52–184] vs 38 [3–153] months,p = 0.04), to have baseline immunocompromise (32 vs 8%,p = 0.006), to have higher PRISM III (13 [8–18] vs 7 [5–13],p = 0.0003) and vasoactive inotrope scores (20 [10–35] vs 10 [3–15],p = 0.0002) scores, and to have more MODS days (3 [1–9] vs 1 [0–3],p = 0.002). Thirty-three subjects had immunoparalysis (TNFα response 78 [52–141] vs 641 [418–1047] pg/ml,p p = 0.0006) whereas no association with MODS duration was seen in children without immunoparalysis (aRR 1.2 [0.6–2.3],p = 0.67).ConclusionHydrocortisone use was independently associated with longer duration of MODS in septic children with immunoparalysis but not in those with more robust immune function. Prospective clinical trials using a priori immunophenotyping are needed to understand optimal hydrocortisone strategies in this population.

OBJECTIVES Nosocomial infection is a common source of morbidity in critically injured children including those with traumatic brain injury. Risk factors for nosocomial infection in this population, however, are poorly understood. We hypothesized that critically ill pediatric trauma patients with traumatic brain injury would demonstrate higher rates of nosocomial infection than those without traumatic brain injury. DESIGN Retrospective case-control study. SETTING PICU, single institution. PATIENTS Patients under 18 years old who were admitted to the PICU for at least 48 hours following a traumatic injury were included. Patients were admitted between September 2008 and December 2015. Patients with the following injury types were excluded: thermal injury, drowning, hanging/strangulation, acute hypoxic ischemic encephalopathy, or nonaccidental trauma. Data collected included demographics, injury information, hospital and PICU length of stay, vital signs, laboratory data, insertion and removal dates for invasive devices, surgeries performed, transfusions of blood products, and microbiology culture results. Initial Pediatric Risk of Mortality III and Pediatric Logistic Organ Dysfunction-2 scores were determined. Patients were classified as having: 1) an isolated traumatic brain injury, 2) a traumatic injury without traumatic brain injury, or 3) polytrauma with traumatic brain injury. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Two hundred three patients were included in the analyses, and 27 patients developed a nosocomial infection. Patients with polytrauma with traumatic brain injury demonstrated a significantly higher infection rate (30%) than patients with isolated traumatic brain injury (6%) or traumatic injury without traumatic brain injury (9%) (p < 0.001). This increased rate of nosocomial infection was noted on univariate analysis, on multivariable analysis, and after adjusting for other risk factors. CONCLUSIONS In this single-center, retrospective analysis of critically ill pediatric trauma patients, nosocomial infections were more frequently observed in patients admitted following polytrauma with traumatic brain injury than in patients with isolated traumatic brain injury or trauma without traumatic brain injury.

Objective To test the hypothesis that early RBC transfusion is associated with duration of organ dysfunction in critically ill septic children. Design Secondary analysis of a single-center prospective observational study. Multivariable negative binomial regression was used to determine relationships between RBC transfusion within 48 hours of sepsis onset and number of days in 14 with organ dysfunction, or with multiple organ dysfunction syndrome. Setting A PICU at a quaternary care children's hospital. Patients Children less than 18 years old with severe sepsis/septic shock by consensus criteria were included. Patients with RBC transfusion prior to sepsis onset and those on extracorporeal membrane oxygenation support within 48 hours of sepsis onset were excluded. Interventions None. Measurements and main results Ninety-four patients were included. Median age was 6 years (0-13 yr); 61% were male. Seventy-eight percentage had septic shock, and 41 (44%) were transfused RBC within 48 hours of sepsis onset (early RBC transfusion). On multivariable analyses, early RBC transfusion was independently associated with 44% greater organ dysfunction days (adjusted relative risk, 1.44 [1.04-2.]; p = 0.03), although risk differed by severity of illness (interaction p = 0.004) and by shock severity (interaction p = 0.04 for Vasoactive Inotrope Score and 0.03 for shock index). Relative risks for multiple organ dysfunction syndrome days varied by shock severity (interaction p = 0.008 for Vasoactive Inotrope Score and 0.01 for shock index). Risks associated with early RBC transfusion were highest for the children with the lowest shock severities. Conclusions In agreement with previous studies, early RBC transfusion was independently associated with longer duration of organ dysfunction. Ours is among the first studies to document different transfusion-associated risks based on clinically available measures of shock severity, demonstrating greater transfusion-associated risks in children with less severe shock. Larger multicenter studies to verify these interaction effects are essential to plan much-needed RBC transfusion trials for critically ill septic children.

BackgroundSevere innate immune suppression, termed immunoparalysis, is associated with increased risks of nosocomial infection and mortality in children with septic shock. Currently, immunoparalysis cannot be clinically diagnosed in children, and mechanisms remain unclear. Transcriptomic studies identify subsets of septic children with downregulation of genes within adaptive immune pathways, but assays of immune function have not been performed as part of these studies, and little is known about transcriptomic profiles of children with immunoparalysis.MethodsWe performed a nested case-control study to identify differences in RNA expression patterns between children with septic shock with immunoparalysis (defined as lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)α response < 200 pg/ml) vs those with normal LPS-induced TNFα response. Children were enrolled within 48 hours of the onset of septic shock and divided into two groups based on LPS-induced TNFα response. RNA was extracted from whole blood for RNAseq, differential expression analyses using DESeq2 software, and pathway analyses using Ingenuity Pathway Analysis.Results32 children were included in analyses. Comparing those with immunoparalysis (n =19) to those with normal TNFα response (n = 13), 2,303 transcripts were differentially expressed with absolute value fold change ≥ 1.5 and false discovery rate ≤ 0.05. The majority of downregulated pathways in children with immunoparalysis were pathways that involved interactions between innate and adaptive immune cells necessary for cell-mediated immunity, crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling pathways. Upregulated pathways included those involved in humoral immunity (T helper cell type 2), corticotropin signaling, platelet activation (GP6 signaling), and leukocyte migration and extravasation.ConclusionsOur study suggests that gene expression data might be useful to identify children with immunoparalysis and identifies several key differentially regulated pathways involved in both innate and adaptive immunity. Our ongoing work in this area aims to dissect interactions between innate and adaptive immunity in septic children and to more fully elucidate patient-specific immunologic pathophysiology to guide individualized immunotherapeutic targets.

OBJECTIVES To serially evaluate health-related quality of life during the first year after community-acquired septic shock in children with preexisting severe developmental disabilities and explore factors associated with health-related quality of life changes in these children. DESIGN Secondary analysis of the Life after Pediatric Sepsis Evaluation investigation. SETTING Twelve academic PICU in the United States. PATIENTS Children greater than or equal to 1 month and less than 18 years old identified by their family caregiver (e.g., parent/guardian) as having severe developmental disability prior to septic shock. INTERVENTIONS Family caregivers completed the Stein-Jessop Functional Status II-R Short Form as a measure of their child's health-related quality of life at baseline (reflecting preadmission status), day 7, and months 1, 3, 6, and 12 following PICU admission. Stein-Jessop Functional Status II-R Short Form scores were linearly transformed to a 0-100 scale, with higher scores indicating better health-related quality of life. MEASUREMENTS AND MAIN RESULTS Of 392 Life after Pediatric Sepsis Evaluation participants, 137 were identified by their caregiver as having a severe developmental disability. Sixteen children (11.6%) with severe disability died during the 12 months following septic shock. Among 121 survivors, Stein-Jessop Functional Status II-R Short Form scores declined from preadmission baseline to day 7 (70.7 ± 16.1 vs 55.6 ± 19.2; p < 0.001). Stein-Jessop Functional Status II-R Short Form scores remained below baseline through month 12 (59.1 ± 21.0, p < 0.001 vs baseline). After adjusting for baseline Stein-Jessop Functional Status II-R Short Form, the caregiver being a single parent/guardian was associated with lower month 3 Stein-Jessop Functional Status II-R Short Form scores (p = 0.041). No other baseline child or caregiver characteristic, or critical illness-related factors were significantly associated with month 3 Stein-Jessop Functional Status II-R Short Form scores. CONCLUSIONS Health-related quality of life among children with severe developmental disability remains, on average, below baseline during the first year following community-acquired septic shock. Children with severe disability and septic shock that are in single parent families are at increased risk. Clinical awareness of the potential for decline in health-related quality of life among disabled children is essential to prevent this adverse outcome from being missed.

The epidemiology of in-hospital death after pediatric sepsis has not been well characterized. We investigated the timing, cause, mode, and attribution of death in children with severe sepsis, hypothesizing that refractory shock leading to early death is rare in the current era.Retrospective observational study.Emergency departments and ICUs at two academic children's hospitals.Seventy-nine patients less than 18 years old treated for severe sepsis/septic shock in 2012-2013 who died prior to hospital discharge.None.Time to death from sepsis recognition, cause and mode of death, and attribution of death to sepsis were determined from medical records. Organ dysfunction was assessed via daily Pediatric Logistic Organ Dysfunction-2 scores for 7 days preceding death with an increase greater than or equal to 5 defined as worsening organ dysfunction. The median time to death was 8 days (interquartile range, 1-12 d) with 25%, 35%, and 49% of cumulative deaths within 1, 3, and 7 days of sepsis recognition, respectively. The most common cause of death was refractory shock (34%), then multiple organ dysfunction syndrome after shock recovery (27%), neurologic injury (19%), single-organ respiratory failure (9%), and nonseptic comorbidity (6%). Early deaths (≤ 3 d) were mostly due to refractory shock in young, previously healthy patients while multiple organ dysfunction syndrome predominated after 3 days. Mode of death was withdrawal in 72%, unsuccessful cardiopulmonary resuscitation in 22%, and irreversible loss of neurologic function in 6%. Ninety percent of deaths were attributable to acute or chronic manifestations of sepsis. Only 23% had a rise in Pediatric Logistic Organ Dysfunction-2 that indicated worsening organ dysfunction.Refractory shock remains a common cause of death in pediatric sepsis, especially for early deaths. Later deaths were mostly attributable to multiple organ dysfunction syndrome, neurologic, and respiratory failure after life-sustaining therapies were limited. A pattern of persistent, rather than worsening, organ dysfunction preceded most deaths.

Rationale: Late immune suppression is associated with nosocomial infection and mortality in adults and children with sepsis. Relationships between early immune suppression and outcomes in children with sepsis remain unclear. Objectives: Prospective observational study to test the hypothesis that early innate and adaptive immune suppression are associated with longer duration of organ dysfunction in children with severe sepsis or septic shock. Methods: Children younger than 18 years of age meeting consensus criteria for severe sepsis or septic shock were sampled within 48 hours of sepsis onset. Healthy control subjects were sampled once. Innate immune function was quantified by whole blood ex vivo LPS-induced TNF-α (tumor necrosis factor-α) production capacity. Adaptive immune function was quantified by ex vivo phytohemagglutinin-induced IFN-γ production capacity. Measurements and Main Results: One hundred two children with sepsis and 35 healthy children were enrolled. Compared with healthy children, children with sepsis demonstrated lower LPS-induced TNF-α production (P