Risk Factors for Persistent Staphylococcus aureus Bacteremia in Children.

BACKGROUND: Staphylococcus aureus is a leading cause of pediatric bacteremia. Persistent S. aureus bacteremia (SAB) is associated with increased morbidity and mortality in adults and children. Risk factors for S. aureus bacteremia have been well established, but there is a limited understanding of the factors that contribute to the development of persistent SAB in children. METHODS: This is a single-center retrospective secondary analysis of a prospective observational study of pediatric patients hospitalized with S. aureus infection over a 3.5-year period at a large, quaternary, children's hospital. RESULTS: Two hundred fifty-nine children with confirmed S. aureus infection were enrolled in the study. Sixty-five of these were found to have bacteremia, with 28 (43%) developing persistent bacteremia. Patients with persistent SAB were culture-positive for a median of 3.5 days compared with 1 day for those without (P ≤ 0.001). Children with persistent SAB were more likely to have an identified osteoarticular source of infection (93%, n = 26 vs. 62%, n = 23; P = 0.008) and had a shorter median duration to culture positivity than those without persistent SAB (16 hours vs. 20 hours; P ≤ 0.001). In addition, children with persistent SAB had higher median values of presenting erythrocyte sedimentation rate, peak erythrocyte sedimentation rate, presenting C-reactive protein and peak C-reactive protein. Not surprisingly, hospital length of stay was longer in children with persistent SAB compared with those without. CONCLUSIONS: These findings suggest that a shorter time to culture positivity, osteoarticular infection, and higher presenting and peak values for select inflammatory markers are potential risk factors for persistent SAB in children.

Toxin-neutralizing Abs are associated with improved T cell function following recovery from Staphylococcus aureus infection.

BACKGROUNDT cell responses are impaired in Staphylococcus aureus-infected children, highlighting a potential mechanism of immune evasion. This study tested the hypotheses that toxin-specific antibodies protect immune cells from bacterial killing and are associated with improved T cell function following infection.METHODSS. aureus-infected and healthy children (N = 33 each) were prospectively enrolled. During acute infection and convalescence, we quantified toxin-specific IgG levels by ELISA, antibody function using a cell killing assay, and functional T cell responses by ELISPOT.RESULTSThere were no differences in toxin-specific IgG levels or ability to neutralize toxin-mediated immune cell killing between healthy and acutely infected children, but antibody levels and function increased following infection. Similarly, T cell function, which was impaired during acute infection, improved following infection. However, the response to infection was highly variable; up to half of children did not have improved antibody or T cell function. Serum from children with higher α-hemolysin-specific IgG levels more strongly protected immune cells against toxin-mediated killing. Importantly, children whose serum more strongly protected against toxin-mediated killing also had stronger immune responses to infection, characterized by more elicited antibodies and greater improvement in T cell function following infection.CONCLUSIONThis study demonstrates that, despite T cell impairment during acute infection, S. aureus elicits toxin-neutralizing antibodies. Individual antibody responses and T cell recovery are variable. These findings also suggest that toxin-neutralizing antibodies protect antigen-presenting cells and T cells, thereby promoting immune recovery. Finally, failure to elicit toxin-neutralizing antibodies may identify children at risk for prolonged T cell suppression.FUNDINGNIH National Institute of Allergy and Infectious Diseases R01AI125489 and Nationwide Children's Hospital.

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.

Measures of Systemic Innate Immune Function Predict the Risk of Nosocomial Infection in Pediatric Burn Patients.

Critical injury-induced immune suppression has been associated with adverse outcomes. This acquired form of immunosuppression is poorly understood in pediatric burn patients, who have infectious complication rates as high as 71%. Our primary objectives were to determine if thermal injury results in early innate immune dysfunction and is associated with increased risk for nosocomial infections (NI). We performed a prospective, longitudinal immune function observational study at a single pediatric burn center. Whole blood samples from burn patients within the first week of injury were used to assess innate immune function. Nosocomial infections were defined using CDC criteria. Immune parameters were compared between patients who went on to develop NI and those that did not. We enrolled a total of 34 patients with 12 developing a NI. Within the first 3 days of injury, children whom developed NI had significantly lower whole blood ex vivo LPS-induced TNFα production capacity (434 pg/mL vs 960 pg/mL, P = .0015), CD14+ monocyte counts (273 cells/µL vs 508 cells/µL, P = .01), and % HLA-DR expression on CD14+ monocytes (54% vs 92%, P = .02) compared with those that did not develop infection. Plasma cytokine levels did not have a significant difference between the NI and no NI groups. Early innate immune suppression can occur following pediatric thermal injury and appears to be a risk factor for the development of nosocomial infections. Plasma cytokines alone may not be a reliable predictor of the development of NI.