Paediatric sepsis survivors are resistant to sepsis-induced long-term immune dysfunction.

BACKGROUND AND PURPOSE: Sepsis-surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, an outcome mediated by the axis IL-33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long-term immune consequences of paediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis. EXPERIMENTAL APPROACH: Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. Likewise, sepsis-surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis-surviving patients were collected and the concentration of IL-33 and Tregs frequency were assessed. KEY RESULTS: In contrast to 6-week-old mice, 2-week-old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in 6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33 production in 2-week-old post-septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in 2-week-old mice. Clinically, adults but not paediatric post-septic patients exhibited higher counts of Tregs and seral IL-33 levels. CONCLUSION AND IMPLICATIONS: These findings demonstrate a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a better understanding of this process may lead to differential treatments for adult and paediatric sepsis.

Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis.

BACKGROUND: Neutrophil extracellular traps (NETs) are innate defense mechanisms that are also implicated in the pathogenesis of organ dysfunction. However, the role of NETs in pediatric sepsis is unknown. METHODS: Infant (2 weeks old) and adult (6 weeks old) mice were submitted to sepsis by intraperitoneal (i.p.) injection of bacteria suspension or lipopolysaccharide (LPS). Neutrophil infiltration, bacteremia, organ injury, and concentrations of cytokine, NETs, and DNase in the plasma were measured. Production of reactive oxygen and nitrogen species and release of NETs by neutrophils were also evaluated. To investigate the functional role of NETs, mice undergoing sepsis were treated with antibiotic plus rhDNase and the survival, organ injury, and levels of inflammatory markers and NETs were determined. Blood samples from pediatric and adult sepsis patients were collected and the concentrations of NETs measured. RESULTS: Infant C57BL/6 mice subjected to sepsis or LPS-induced endotoxemia produced significantly higher levels of NETs than the adult mice. Moreover, compared to that of the adult mice, this outcome was accompanied by increased organ injury and production of inflammatory cytokines. The increased NETs were associated with elevated expression of Padi4 and histone H3 citrullination in the neutrophils. Furthermore, treatment of infant septic mice with rhDNase or a PAD-4 inhibitor markedly attenuated sepsis. Importantly, pediatric septic patients had high levels of NETs, and the severity of pediatric sepsis was positively correlated with the level of NETs. CONCLUSION: This study reveals a hitherto unrecognized mechanism of pediatric sepsis susceptibility and suggests that NETs represents a potential target to improve clinical outcomes of sepsis.

Epidemiology and Outcome of Acute Kidney Injury According to Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease and Kidney Disease: Improving Global Outcomes Criteria in Critically Ill Children-A Prospective Study.

OBJECTIVE: We aimed to investigate the epidemiology, risk factors, and short- and medium-term outcome of acute kidney injury classified according to pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease, and Kidney Disease: Improving Global Outcomes criteria in critically ill children. DESIGN: Prospective observational cohort study. SETTING: Two eight-bed PICUs of a tertiary-care university hospital. PATIENTS: A heterogeneous population of critically ill children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, clinical, laboratory, and outcome data were collected on all patients admitted to the PICUs from August 2011 to January 2012, with at least 24 hours of PICU stay. Of the 214 consecutive admissions, 160 were analyzed. The prevalence of acute kidney injury according to pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease and Kidney Disease: Improving Global Outcomes criteria was 49.4% vs. 46.2%, respectively. A larger proportion of acute kidney injury episodes was categorized as Kidney Disease: Improving Global Outcomes stage 3 (50%) compared with pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease F (39.2%). Inotropic score greater than 10 was a risk factor for acute kidney injury severity. About 35% of patients with acute kidney injury who survived were discharged from the PICU with an estimated creatinine clearance less than 75 mL/min/1.73 m and one persisted with altered renal function 6 months after PICU discharge. Age 12 months old or younger was a risk factor for estimated creatinine clearance less than 75 mL/min/1.73 m at PICU discharge. Acute kidney injury and its severity were associated with increased PICU length of stay and longer duration of mechanical ventilation. Eleven patients died; nine had acute kidney injury (p < 0.05). The only risk factor associated with death after multivariate adjustment was Pediatric Risk of Mortality score greater than or equal to 10. CONCLUSIONS: Acute kidney injury defined by both pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease and Kidney Disease: Improving Global Outcomes criteria was associated with increased morbidity and mortality, and may lead to long-term renal dysfunction.

Diagnostic and prognostic value of serum cystatin C in critically ill children with acute kidney injury.

OBJECTIVES: We aimed to evaluate the value of serum cystatin C for detection of acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories in critically ill children and to investigate whether serum cystatin C was associated with outcome. DESIGN: Prospective cohort study. SETTING: PICU of a tertiary-care university hospital. PATIENTS: A heterogeneous population of critically ill children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood and 24-hour urine samples were collected daily over the first 2 days after PICU admission for measurement of serum cystatin C, serum creatinine, and creatinine clearance. Acute kidney injury was classified by pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease criteria. One hundred twenty-two children were prospectively enrolled; 40 (32.8%) developed acute kidney injury. Serum cystatin C was higher in patients with acute kidney injury compared with those who did not develop acute kidney injury at PICU admission (median, 0.90 mg/L vs 0.51 mg/L) and on the first (1.12 mg/L vs 0.57 mg/L) and second PICU days (1.15 mg/L vs 0.58 mg/L). Serum creatinine was higher in acute kidney injury group only on the first (0.50 mg/dL vs 0.40 mg/dL) and second PICU days (0.60 mg/dL vs 0.40 mg/dL). Serum cystatin C was increasingly higher according to acute kidney injury severity (Failure > Injury > Risk). Area under the receiver operating characteristic curve of cystatin C for acute kidney injury detection was 0.89. Serum cystatin C greater than 0.70 mg/L was associated with longer length of PICU stay (adjusted hazard ratio, 1.64) and prolonged duration of mechanical ventilation (adjusted hazard ratio, 1.82). CONCLUSIONS: Cystatin C is an early and accurate biomarker for acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories, and it is associated with adverse clinical outcomes in a heterogeneous population of critically ill children.