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.
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.
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.
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).
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.
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
With rapid and accurate molecular influenza testing now widely available in clinical settings, influenza vaccine effectiveness (VE) studies can prospectively select participants for enrollment based ...on real-time results rather than enrolling all eligible patients regardless of influenza status, as in the traditional test-negative design (TND). Thus, we explore advantages and disadvantages of modifying the TND for estimating VE by using real-time, clinically available viral testing results paired with acute respiratory infection eligibility criteria for identifying influenza cases and test-negative controls prior to enrollment. This modification, which we have called the real-time test-negative design (rtTND), has the potential to improve influenza VE studies by optimizing the case-to-test-negative control ratio, more accurately classifying influenza status, improving study efficiency, reducing study cost, and increasing study power to adequately estimate VE. Important considerations for limiting biases in the rtTND include the need for comprehensive clinical influenza testing at study sites and accurate influenza tests.
Influenza virus is a major cause of acute hypoxemic respiratory failure. Early identification of patients who will suffer severe complications can help stratify patients for clinical trials and plan ...for resource use in case of pandemic.
We aimed to identify which clinical variables best predict prolonged acute hypoxemic respiratory failure in influenza-infected critically ill children. Acute hypoxemic respiratory failure was defined using hypoxemia cutoffs from international consensus definitions of acute respiratory distress syndrome in patients with ventilatory support. Prolonged acute hypoxemic respiratory failure was defined by acute hypoxemic respiratory failure criteria still present at PICU day 7.
In this prospective multicenter study across 34 PICUs from November 2009 to April 2018, we included children (< 18 yr) without comorbid risk factors for severe disease.
We used a Monte Carlo cross validation method with
random train-test splits at a 70-30% proportion per model.
Using clinical data at admission (day 1) and closest to 8 am on PICU day 2, we calculated the area under the receiver operating characteristic curve using random forests machine learning algorithms and logistic regression.
We included 258 children (median age = 6.5 yr) and 11 (4.2%) died. By day 2, 65% (
= 165) had acute hypoxemic respiratory failure dropping to 26% (
= 67) with prolonged acute hypoxemic respiratory failure by day 7. Those with prolonged acute hypoxemic respiratory failure had a longer ICU stay (16.5 vs 4.0 d;
< 0.001) and higher mortality (13.4% vs 1.0%). A multivariable model using random forests with 10 admission and eight day 2 variables performed best (0.93 area under the receiver operating characteristic curve; 95 CI%: 0.90-0.95) where respiratory rate, Fio
, and pH on day 2 were the most important factors.
In this prospective multicentric study, most children with influenza virus-related respiratory failure with prolonged acute hypoxemic respiratory failure can be identified early in their hospital course applying machine learning onto routine clinical data. Further validation is needed prior to bedside implementation.
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