Myeloid-derived suppressor cells and T cell populations in children with Multisystem Inflammatory Syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) represents a hyperinflammatory state that can result in multi-organ dysfunction and death. Myeloid-derived suppressor cells (MDSC) are an immunosuppressive cell population that expands under inflammatory conditions and suppresses T cell function. We hypothesized that MDSC would be increased in children with MIS-C and that MDSC expansion would be associated with T cell lymphopenia. METHODS: We conducted a prospective, observational study. Initial blood samples were collected within 48 h of admission. Age-matched healthy controls underwent sampling once. MDSC and T cell populations were identified by flow cytometric methods. RESULTS: We enrolled 22 children with MIS-C (12 ICU, 10 ward) and 21 healthy controls (HC). Children with MIS-C demonstrated significantly higher MDSC compared to HC, and MDSC expansion persisted for >3 weeks in the ICU group. Children with MIS-C admitted to the ICU demonstrated significantly lower absolute numbers of T cells and natural killer cells. There were no significant associations between MDSC and cardiac dysfunction, duration of hospitalization, or vasoactive inotrope score. CONCLUSIONS: Our study suggests that children critically ill with MIS-C have expansion of MDSC and associated decreased T cell and NK cell populations. Our results did not demonstrate associations between MDSC and clinical outcomes. IMPACT: Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated immune response occurring several weeks after SARS-CoV-2 infection that can result in multi-organ dysfunction and death. Children severely ill with MIS-C demonstrated increased myeloid-derived suppressor cells and decreased absolute numbers of CD4+ and CD8 + T cells and NK cells compared to healthy controls. There was no significant association between MDSC numbers and clinical outcomes; including cardiac dysfunction, length of stay, or requirement of vasoactive support, in children with MIS-C.

Impaired T-Lymphocyte Responses During Childhood Staphylococcus aureus Infection.

BACKGROUND: Staphylococcus aureus infections are common throughout the lifespan, with recurrent infections occurring in nearly half of infected children. There is no licensed vaccine, underscoring the need to better understand how S. aureus evades protective immunity. Despite much study, the relative contributions of antibodies and T cells to protection against S. aureus infections in humans are not fully understood. METHODS: We prospectively quantified S. aureus-specific antibody levels by ELISA and T-cell responses by ELISpot in S. aureus-infected and healthy children. RESULTS: S. aureus-specific antibody levels and T-cell responses increased with age in healthy children, suggesting a coordinated development of anti-staphylococcal immunity. Antibody levels against leukotoxin E (LukE) and Panton-Valentine leukocidin (LukS-PV), but not α-hemolysin (Hla), were higher in younger infected children, compared with healthy children; these differences disappeared in older children. We observed a striking impairment of global and S. aureus-specific T-cell function in children with invasive and noninvasive infection, suggesting that S. aureus-specific immune responses are dysregulated during childhood infection regardless of the infection phenotype. CONCLUSIONS: These findings identify a potential mechanism by which S. aureus infection actively evades adaptive immune responses, thereby preventing the development of protective immunity and maintaining susceptibility to recurrent infection.

Novel Identification of Myeloid-Derived Suppressor Cells in Children With Septic Shock.

OBJECTIVES: Immunoparalysis in children with septic shock is associated with increased risk of nosocomial infections and death. Myeloid-derived suppressor cells (MDSCs) potently suppress T cell function and may perpetuate immunoparalysis. Our goal was to test the hypothesis that children with septic shock would demonstrate increased proportions of MDSCs and impaired immune function compared with healthy controls. DESIGN: Prospective observational study. SETTING: Fifty-four bed PICU in a quaternary-care children's hospital. PATIENTS: Eighteen children with septic shock and thirty age-matched healthy children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and stained for cell surface markers to identify MDSCs by flow cytometric analysis, including granulocytic and monocytic subsets. Adaptive and innate immune function was measured by ex vivo stimulation of whole blood with phytohemagglutinin-induced interferon (IFN) γ production and lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production, respectively. Prolonged organ dysfunction (OD) was defined as greater than 7 days. Children with septic shock had a higher percentage of circulating MDSCs, along with lower LPS-induced TNFα and phytohemagglutinin-induced IFNγ production capacities, compared with healthy controls. A cut-off of 25.2% MDSCs of total PBMCs in initial samples was optimal to discriminate children with septic shock who went on to have prolonged OD, area under the curve equal to 0.86. Children with prolonged OD also had decreased TNFα production capacity over time compared with those who recovered more quickly ( p = 0.02). CONCLUSIONS: This article is the first to describe increased MDSCs in children with septic shock, along with an association between early increase in MDSCs and adverse OD outcomes in this population. It remains unclear if MDSCs play a causative role in sepsis-induced immune suppression in children. Additional studies are warranted to establish MDSC as a potential therapeutic target.

A Core Outcome Measurement Set for Pediatric Critical Care.

OBJECTIVES: To identify a PICU Core Outcome Measurement Set (PICU COMS), a set of measures that can be used to evaluate the PICU Core Outcome Set (PICU COS) domains in PICU patients and their families. DESIGN: A modified Delphi consensus process. SETTING: Four webinars attended by PICU physicians and nurses, pediatric surgeons, rehabilitation physicians, and scientists with expertise in PICU clinical care or research ( n = 35). Attendees were from eight countries and convened from the Pediatric Acute Lung Injury and Sepsis Investigators Pediatric Outcomes STudies after PICU Investigators and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network PICU COS Investigators. SUBJECTS: Measures to assess outcome domains of the PICU COS are as follows: cognitive, emotional, overall (including health-related quality of life), physical, and family health. Measures evaluating social health were also considered. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measures were classified as general or additional based on generalizability across PICU populations, feasibility, and relevance to specific COS domains. Measures with high consensus, defined as 80% agreement for inclusion, were selected for the PICU COMS. Among 140 candidate measures, 24 were delineated as general (broadly applicable) and, of these, 10 achieved consensus for inclusion in the COMS (7 patient-oriented and 3 family-oriented). Six of the seven patient measures were applicable to the broadest range of patients, diagnoses, and developmental abilities. All were validated in pediatric populations and have normative pediatric data. Twenty additional measures focusing on specific populations or in-depth evaluation of a COS subdomain also met consensus for inclusion as COMS additional measures. CONCLUSIONS: The PICU COMS delineates measures to evaluate domains in the PICU COS and facilitates comparability across future research studies to characterize PICU survivorship and enable interventional studies to target long-term outcomes after critical illness.

Adaptations of transfusion systems to the COVID-19 pandemic in British Columbia, Canada: Early experiences of a large tertiary care center and survey of provincial activities.

BACKGROUND: In March 2020, a state of emergency was declared to facilitate organized responses to the coronavirus disease 2019 (COVID-19) pandemic in British Columbia, Canada. Emergency blood management committees (EBMCs) were formed regionally and provincially to coordinate transfusion service activities and responses to possible national blood shortages. STUDY DESIGN AND METHODS: We describe the responses of transfusion services to COVID-19 in regional health authorities in British Columbia through a collaborative survey, contingency planning meeting minutes, and policy documents, including early trends observed in blood product usage. RESULTS: Early strategic response policies were developed locally in collaboration with members of the provincial EBMC and focused on three key areas: utilization management strategies, stakeholder engagement (collaboration with frequent users of the transfusion service, advance notification of potential inventory shortage plans, and development of blood triage guidance documents), and laboratory staffing and infection control procedures. Reductions in transfusion volumes were observed beginning in mid-March 2020 for red blood cells and platelets relative to the prepandemic baseline (27% and 26% from the preceding year, respectively). There was a slow gradual return toward baseline beginning one month later; no product shortage issues were experienced. CONCLUSION: Provincial collaborative efforts facilitated the development of initiatives focused on minimizing potential COVID-19-related disruptions in transfusion services in British Columbia. While there have been no supply issues to date, the framework developed early in the pandemic should facilitate timely responses to possible disruptions in future waves of infection.

Escherichia coli bloodstream infections in the western interior of British Columbia, Canada: a population-based cohort study.

Our population-based study objectives were to describe characteristics and outcomes of Escherichia coli bloodstream infections (BSIs), and to evaluate factors associated with outcomes. We included incident E. coli BSIs from western interior residents (British Columbia, Canada; 04/2010-03/2020). We obtained data including patient demographics, location of onset, infection focus, Charlson comorbidity index (CCI), antimicrobial resistance, 30-day all-cause mortality and length of hospital stay (LOS). Using multivariable logistic regression models fitted with generalised estimating equations, we estimated factors associated with 30-day mortality and long post-infection LOS (>75th percentile). We identified 1080 incident E. coli BSIs in 1009 patients. The crude incidence and 30-day mortality rates were 59.1 BSIs and 6.8 deaths/100 000 person-years, respectively. The 30-day case fatality risk was 11.5%. Compared to community-acquired E. coli BSIs, either healthcare-associated or nosocomial cases had higher odds of 30-day mortality. Older cases, non-urogenital BSI foci and CCI ⩾ 3 had higher odds of 30-day mortality compared to younger cases, urogenital foci and CCI < 3. In patients that survived to discharge, those with extended-spectrum ß-lactamase (ESBL)-producing E. coli BSIs, nosocomial BSIs, and CCI ⩾ 3 had higher odds of long post-infection LOS compared to those with non-ESBL-producing, community-acquired and healthcare-associated, and CCI < 3. There is a substantial disease burden from E. coli BSIs.

Burden of bloodstream infection in older persons: a population-based study.

BACKGROUND: Advancing age is a major risk factor for developing and dying from bloodstream infections (BSI). However, there is a paucity of population-based studies investigating the epidemiology of BSI in older persons. OBJECTIVE: To define the incidence, clinical determinants, and risk factors for death among those aged 65 years and older with BSI. METHODS: Population-based surveillance was conducted in the western interior of British Columbia, Canada, between April 1, 2010 and March 31, 2020. Chart reviews were conducted for clinical details and all cause case-fatality was established at 30-days follow-up. RESULTS: A total of 1854 incident BSI were identified among 1657 individuals aged 65 and older for an annual incidence of 533.9 per 100,000 population; the incidence for those aged 65-74, 75-84, and ≥85 years was 375.3, 678.9, and 1046.6 per 100,000 population, respectively. Males were at significantly increased risk as compared to females (incidence rate ratio, IRR 1.44; 95% confidence interval, CI, 1.32-1.59; p<0.0001). The crude annual incidence increased by 50% during the study. However, this was related to shift in population demographics with no increase evident following age- and sex-standardization. Older patients were more likely to have healthcare-associated infections and genitourinary sources and less likely to have bone/joint or soft tissue infections. The proportion of patients with underlying congestive heart failure, stroke, and dementia increased, whereas diabetes and liver disease decreased with older age. The overall 30-day all cause case-fatality rate was 22.0% (364/1657). After adjustment for clinical focus, onset of infection, etiology, and co-morbidity in a logistic model, those aged 75-84 years (odds ratio, OR, 1.66; 95% CI, 1.25-2.21) and ≥ 85 years (OR, 1.98; 95% CI, 1.41-2.77) were at significantly increased risk for death as compared to those aged 65-74 years. CONCLUSION: Bloodstream infection is common in older persons and is a major cause of death. Countries with aging populations worldwide should expect an increase burden associated with BSI in the coming years.

A Randomized Study Using Telepresence Robots for Behavioral Health in Interprofessional Practice and Education.

Background: The events of the coronavirus disease 2019 (COVID-19) pandemic forced the world to adopt telemedicine frameworks to comply with isolation and stay-at-home regulations. Telemedicine, in various forms, has been used by patients and medical professionals for quite some time, especially telepsychiatry. To examine the efficacy and role of telesimulation as a method to educate health sciences students via telepresence robots. The study recruited students from the above health science disciplines. All participants were trained to administer a contextual interview to a standardized patient (SP) for mental health concerns. Methods: The completion of the contextual interview observation form adult (CIOF-A), National Aeronautics and Space Administration Task Load Index, self-efficacy in patient centeredness questionnaire (SEPCQ), and communication skills attitude scale with or without a telepresence robot. All participants completed baseline metrics and were trained to conduct a contextual interview to an SP. Researchers block-randomized the participants to either the telepresence robot group (TP) or in-person (IP) group. Results: The study recruited n = 43 participants to the IP group (n = 21) or TP group (n = 22). Mean participant demographics of age were 25.3 (±1.9) years in the IP group and 24.3 (±2.1) years for the TP group. Mean and standard deviation scores with effect sizes in CIOF-A scores IP: 0.05 (±1.91) and TP: -0.45 (±1.71), Cohen's d = 0.28; SEPCQ-Patient Domain scores IP: 0.42 (±4.69) and TP: 0.50 (±7.18), Cohen's d = 0.01; change in SEPCQ-Sharing Domain scores IP: 0.53 (±5.10) and TP: 0.91 (±9.98), Cohen's d = 0.05. These effect sizes will inform future studies and appropriate sample sizes. Conclusion: These data indicate that health sciences students utilizing a telepresence robot in an SP scenario to perform a behavioral health screening felt as comfortable and competent as those health sciences students performing the same behavioral health screening in person. ClinicalTrials.gov Identifier: NCT03661372.

Population-based risk factors for community-onset bloodstream infections.

Although a number of comorbidities have been associated with development of bloodstream infection, actual risk factors have not been well defined and quantified in nonselected populations. We sought to quantify population-based risk factors for development of community-onset bloodstream infection (COBSI). Surveillance was conducted among all residents of the Western Interior of British Columbia, Canada, during 2011-2018. Risks were expressed as incidence rate ratios (IRR) with 95% confidence intervals (CI). The annual incidence was 147.1 per 100,000 and older individuals, and males were at overall higher risk. The median Charlson score was 2 (IQR, 0-3), and this was higher among those with healthcare-associated (2; IQR, 1-4) as compared to community-associated (1; IQR, 0-2; P < 0.0001) COBSI. Risk factors for development of COBSI included (IRR; 95% CI): HIV infection (8.89; 5.17-14.27), cancer (6.80; 6.13-7.54), congestive heart failure (4.68; 4.00-5.46), dementia (3.31; 2.82-3.87), diabetes mellitus (3.10; 2.80-3.42), cerebrovascular accident (2.79; 2.34-3.31), renal dysfunction (2.75; 2.33-3.22), chronic lung disease (2.03; 1.79-2.28), peripheral vascular disease (1.68; 1.39-2.01), and rheumatic disease (1.44; 1.14-1.79). Patients with multiple comorbid illnesses were older, more likely to be male, and have healthcare-associated BSI, higher rates of antimicrobial resistance, and different clinical foci of infection. A number of demographic and comorbid conditions significantly increase the risk for development of COBSI.

Risk of bloodstream infection in patients with renal dysfunction: a population-based cohort study.

Although patients with end-stage renal disease (ESRD) are known to be at high risk for developing bloodstream infections (BSI), the risk associated with lesser degrees of renal dysfunction is not well defined. We sought to determine the risk for acquiring and dying from community-onset BSIs among patients with renal dysfunction. A retrospective, population-based cohort study was conducted among adult residents without ESRD in the western interior of British Columbia. Estimated glomerular filtration rates (eGFR) were determined for cases and incidence rate ratios (IRR) were calculated using prevalence estimates. Overall, 1553 episodes of community-onset BSI were included of which 39%, 32%, 17%, 9%, 2% and 1% had preceding eGFRs of ≥90, 60-89, 45-59, 30-44, 15-29 and <15 ml/min/m2, respectively. As compared to those with eGFR ≥60 ml/min/m2, patients with eGFR 30-59 ml/min/m2 (IRR 4.4; 95% confidence interval (CI) 3.9-4.9) and eGFR <30 ml/min/m2 (IRR 7.0; 95% CI 5.0-9.5) were at significantly increased risk for the development of community-onset BSI. An eGFR <30 ml/min/m2 was an independent risk factor for death (odds ratio 2.3; 95% CI 1.01-5.15). Patients with renal dysfunction are at increased risk for developing and dying from community-onset BSI that is related to the degree of dysfunction.

Hydrocortisone treatment is associated with a longer duration of MODS in pediatric patients with severe sepsis and immunoparalysis.

BACKGROUND: Severe 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. METHODS: Children 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 < 200 pg/ml being diagnostic of immunoparalysis. The primary outcome measure was number of days in 14 with MODS. Univariate and multivariable negative binomial regression models were used to examine associations between hydrocortisone use, immune function, and duration of MODS. RESULTS: One 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 < 0.0001). Hydrocortisone use was associated with longer duration of MODS in children with immunoparalysis after adjusting for covariables (aRR 3.7 [1.8-7.9], 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). CONCLUSION: Hydrocortisone 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.

Shock Severity Modifies Associations Between RBC Transfusion in the First 48 Hours of Sepsis Onset and the Duration of Organ Dysfunction in Critically Ill Septic Children.

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.

Bloodstream infection due to ß-hemolytic streptococci: a population-based comparative analysis.

PURPOSE: Although the burden of illness due to Streptococcus pyogenes is widely recognized, other ß-hemolytic streptococci are also important causes of invasive infections. The objective of this study was to compare the population-based epidemiology of groups A, B, and C/G ß-hemolytic streptococcal bloodstream infection (BSI). METHODS: Population-based surveillance was conducted in the western interior of British Columbia, Canada, 2011-2018. RESULTS: A total of 210 episodes were identified for an incidence of 14.4 per 100,000; the incidences of groups A, B and C/G streptococcal BSI were 4.2, 4.7, and 5.5 per 100,000, respectively. There was an increasing annual incidence of ß-hemolytic streptococcal BSI from 2011 through to a peak incidence in 2016 that decreased thereafter. Fifty-two percent (110) of BSIs were community associated, 43% (91) were healthcare associated, and 4% (9) were hospital onset. Patients with group A were younger, more likely to be female, and have fewer co-morbidities than patients with groups B and C/G streptococcal BSI. The most common focus of infection was soft tissue (109/52%), followed by primary (33; 16%), and bone and joint (20; 10%) and these varied by streptococcal species (p < 0.001). The 30-day all-cause case fatality rate was 11% (24/210) and did not significantly vary by group (p = 0.7). CONCLUSION: Although the determinants vary, the overall burden of disease related to BSI is similar amongst groups A, B and C/G ß-hemolytic streptococci.

Occurrence and determinants of Klebsiella species bloodstream infection in the western interior of British Columbia, Canada.

BACKGROUND: Klebsiella species are among the most common causes of bloodstream infection (BSI). However, few studies have evaluated their epidemiology in non-selected populations. The objective was to define the incidence of, risk factors for, and outcomes from Klebsiella species BSI among residents of the western interior of British Columbia, Canada. METHODS: Population-based surveillance was conducted between April 1, 2010 and March 31, 2017. RESULTS: 151 episodes were identified for an incidence of 12.1 per 100,000 population per year; the incidences of K. pneumoniae and K. oxytoca were 9.1 and 2.9 per 100,000 per year, respectively. Overall 24 (16%) were hospital-onset, 90 (60%) were healthcare-associated, and 37 (25%) were community-associated. The median patient age was 71.4 (interquartile range, 58.8-80.9) years and 88 (58%) cases were males. Episodes were uncommon among patients aged < 40 years old and no cases were observed among those aged < 10 years. A number of co-morbid medical illnesses were identified as significant risks and included (incidence rate ratio; 95% confidence interval) cerebrovascular accident (5.9; 3.3-9.9), renal disease 4.3; 2.5-7.0), cancer (3.8; 2.6-5.5), congestive heart failure (3.5; 1.6-6.6), dementia (2.9; 1.5-5.2), diabetes mellitus (2.6; 1.7-3.9), and chronic obstructive pulmonary disease (2.3; 1.5-3.5). Of the 141 (93%) patients admitted to hospital, the median hospital length stay was 8 days (interquartile range, 4-17). The in-hospital and 30-day all cause case-fatality rates were 24/141 (17%) and 27/151 (18%), respectively. CONCLUSIONS: Klebsiella species BSI is associated with a significant burden of illness particularly among those with chronic co-morbid illnesses.

Early Immune Function and Duration of Organ Dysfunction in Critically III Children with Sepsis.

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 < 0.0001) and lower phytohemagglutinin-induced IFN-γ production (P < 0.0001). Among children with sepsis, early innate and adaptive immune suppression were associated with greater number of days with multiple organ dysfunction syndrome and greater number of days with any organ dysfunction. On multivariable analyses, early innate immune suppression remained independently associated with increased multiple organ dysfunction syndrome days (adjusted relative risk, 1.2; 95% confidence interval, 1.03-1.5) and organ dysfunction days (adjusted relative risk, 1.2; 95% confidence interval, 1.1-1.3). CONCLUSIONS: Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early innate and adaptive immune suppression are associated with longer durations of organ dysfunction and may be useful markers to help guide future investigations of immunomodulatory therapies in children with sepsis.

Red blood cell transfusion and immune function in critically ill children: a prospective observational study.

BACKGROUND: Our previous in vitro work showed that stored red blood cells (RBCs) increasingly suppress markers of innate immune function with increased storage time. This multicenter prospective observational study tests the hypothesis that a single RBC transfusion in critically ill children is associated with immune suppression as a function of storage time. STUDY DESIGN AND METHODS: Blood samples were taken immediately before and 24 (±6) hours after a single RBC transfusion ordered as part of routine care. Innate and adaptive immune function was assessed by ex vivo whole blood stimulation with lipopolysaccharide (LPS) and phytohemagglutinin, respectively. Monocyte HLA-DR expression, regulatory T cells, plasma interleukin (IL)-6, and IL-8 levels were also measured. RESULTS: Thirty-one transfused critically ill children and eight healthy controls were studied. Critically ill subjects had lower pretransfusion LPS-induced tumor necrosis factor-α production capacity compared to healthy controls, indicating innate immune suppression (p < 0.0002). Those who received RBCs stored for not more than 21 days demonstrated recovery of innate immune function (p = 0.02) and decreased plasma IL-6 levels (p = 0.002) over time compared to children transfused with older blood, who showed persistence of systemic inflammation and innate immune suppression. RBC storage time was not associated with changes in adaptive immune function. CONCLUSION: In this pilot cohort of critically ill children, transfusion with older prestorage leukoreduced RBCs was associated with persistence of innate immune suppression and systemic inflammation. This was not seen with fresher RBCs. RBC transfusion had no short-term association with adaptive immune function. Further studies are warranted to confirm these findings in a larger cohort of patients.

Early adaptive immune suppression in children with septic shock: a prospective observational study.

INTRODUCTION: Innate immune suppression occurs commonly in pediatric critical illness, in which it is associated with adverse outcomes. Less is known about the adaptive immune response in critically ill children with sepsis. We designed a single-center prospective, observational study to test the hypothesis that children with septic shock would have decreased adaptive immune function compared with healthy children and that among children with sepsis, lower adaptive immune function would be associated with the development of persistent infection or new nosocomial infection. METHODS: Children (18 years or younger) who were admitted to the pediatric intensive care unit with septic shock (by International Consensus Criteria) were enrolled in the study. Blood samples were taken within 48 hours of sepsis onset and again on Day 7 of illness. Adaptive immune function was assessed with ex vivo phytohemagglutinin (PHA)-induced cytokine production capacity of isolated CD4+ T cells. Percentage of regulatory T cells was measured with flow cytometry. Absolute lymphocyte counts were recorded when available. RESULTS: In total, 22 children with septic shock and eight healthy controls were enrolled. Compared with those from healthy children, CD4+ T cells isolated from septic shock children on Days 1 to 2 of illness and stimulated with PHA produced less of the pro-inflammatory cytokine interferon gamma (IFN-γ) (P = 0.002), and the antiinflammatory cytokines interleukin (IL)-4 (P = 0.03) and IL-10 (P = 0.02). Among septic shock children, those who went on to develop persistent or nosocomial infection had decreased T-cell ex vivo PHA-induced production of IFN-γ (P = 0.01), IL-2 (P = 0.01), IL-4 (P = 0.008), and IL-10 (P = 0.001) compared with septic shock children who did not. Percentage of regulatory T cells (CD4+CD25+CD127lo) did not differ among groups. CONCLUSIONS: Adaptive immune suppression may occur early in the course of pediatric septic shock and is associated with adverse infection-related outcomes.

FAS(APO), DAMP, and AKT Phosphoproteins Expression Predict the Development of Nosocomial Infection After Pediatric Burn Injury.

Pediatric burn injuries are a leading cause of morbidity with infections being the most common acute complication. Thermal injuries elicit a heightened cytokine response while suppressing immune function; however, the mechanisms leading to this dysfunction are still unknown. Our aim was to identify extracellular proteins and circulating phosphoprotein expression in the plasma after burn injury to predict the development of nosocomial infection (NI). Plasma was collected within 72 hours after injury from sixty-four pediatric burn subjects; of these, eighteen went on to develop a NI. Extracellular damage associated molecular proteins (DAMPs), FAS(APO), and protein kinase b (AKT) signaling phosphoproteins were analyzed. Subjects who went on to develop a NI had elevated high mobility group box 1 (HMGB1), heat shock protein 90 (HSP90), and FAS expression than those who did not develop a NI after injury (NoNI). Concurrently, phosphorylated (p-) AKT and mammalian target of rapamycin (p-mTOR) were elevated in those subjects who went on to develop a NI. Quadratic discriminant analysis revealed distinct differential profiles between NI and NoNI burn subjects using HSP90, FAS, and p-mTOR. The area under the receiver-operator characteristic curves displayed significant ability to distinguish between these two burn subject cohorts. These findings provide insight into predicting the signaling proteins involved in the development of NI in pediatric burn patients. Further these proteins show promise as a diagnostic tool for pediatric burn patients at risk of developing infection while additional investigation may lead to potential therapeutics to prevent NI.

Multidisciplinary quality improvement initiative to reduce ventilator-associated tracheobronchitis in the PICU.

OBJECTIVE: To test the hypothesis that successful implementation of a care bundle designed to prevent nosocomial airway infection will be associated with decreased incidence of ventilator-associated tracheobronchitis. DESIGN: Prospective pre- and post interventional. SETTING: PICU at an academic medical center PATIENTS: : All patients admitted to the PICU who received invasive mechanical ventilation for greater than or equal to 48 hours between March 1, 2009, and December 31, 2011. INTERVENTION: Multidisciplinary, unit wide implementation of an evidence-based care bundle to prevent ventilator-associated airway infection. MEASUREMENTS AND MAIN RESULTS: There were 725 patients included in the analysis (338 patients preintervention and 387 patients postintervention). Baseline ventilator-associated tracheobronchitis rate in the preintervention period was 3.9 cases per 1,000 ventilator days compared with 1.8 cases per 1,000 ventilator days postintervention (p = 0.04, Fisher exact test). Compared with patients without ventilator-associated tracheobronchitis or ventilator-associated pneumonia, patients with ventilator-associated tracheobronchitis had fewer ventilator-free days in 28 days (4.9 vs 22; p < 0.0001, Mann-Whitney U test) and fewer ICU-free days in 28 days (0.5 vs 19; p < 0.0001, Mann-Whitney U test). These relationships remained significant after adjusting for covariates by multivariable linear regression. CONCLUSIONS: Successful implementation of a care bundle to prevent ventilator-associated infection was associated with decreased incidence of ventilator-associated tracheobronchitis. Development of ventilator-associated tracheobronchitis was independently associated with adverse outcomes in our cohort of pediatric ICU patients.