Innate Immune Function and Mortality in Critically Ill Children With Influenza: A Multicenter Study*
ABSTRACT OBJECTIVE:: To prospectively evaluate relationships among serum cytokine levels, innate immune responsiveness, and mortality in a multicenter cohort of critically ill children with influenza infection. DESIGN:: Prospective, multicenter, observational study. SETTING:: Fifteen pediatric ICUs among members of the Pediatric Acute Lung Injury and Sepsis Investigators network. PATIENTS:: Patients ≤18 yrs old admitted to a PICU with community-acquired influenza infection. A control group of outpatient children was also evaluated. INTERVENTIONS:: ICU patients underwent sampling within 72 hrs of ICU admission for measurement of a panel of 31 serum cytokine levels and quantification of whole blood ex vivo lipopolysaccharide-stimulated tumor necrosis factor-α production capacity using a standardized stimulation protocol. Outpatient control subjects also underwent measurement of tumor necrosis factor-α production capacity. MEASUREMENTS AND MAIN RESULTS:: Fifty-two patients (44 survivors, eight deaths) were sampled. High levels of serum cytokines (granulocyte macrophage colony-stimulating factor, interleukin-6, interleukin-8, interferon-inducible protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α) were associated with mortality (p < 0.0016 for each comparison) as was the presence of secondary infection with Staphylococcus aureus (p = 0.007), particularly methicillin-resistant S. aureus (p < 0.0001). Nonsurvivors were immunosuppressed with leukopenia and markedly reduced tumor necrosis factor-α production capacity compared with outpatient control subjects (n = 21, p < 0.0001) and to ICU survivors (p < 0.0001). This association remained after controlling for multiple covariables. A tumor necrosis factor-α response <250 pg/mL was highly predictive of death and longer duration of ICU stay (p < 0.0001). Patients with S. aureus coinfection demonstrated the greatest degree of immunosuppression (p < 0.0001). CONCLUSIONS:: High serum levels of cytokines can coexist with marked innate immune suppression in children with critical influenza. Severe, early innate immune suppression is highly associated with both S. aureus coinfection and mortality in this population. Multicenter innate immune function testing is feasible and can identify these high-risk children.
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ABSTRACT: Innate immune suppression occurs commonly in pediatric critical illness, where it is associated with adverse outcomes. Less is known about the adaptive immune response in critically ill septic children. We designed a single-center prospective, observational study to test the hypothesis that children with septic shock would have decreased adaptive immune function compared to healthy children and that among septic children, lower adaptive immune function would be associated with the development of persistent infection or new nosocomial infection.Critical Care 07/2014; 18(4):R145. DOI:10.1186/cc13980 · 5.04 Impact Factor
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ABSTRACT: Critical injury has been associated with reduction in innate immune function in adults, with infection risk being related to degree of immune suppression. This relationship has not been reported in critically injured children.Shock 06/2014; 42(4):313-21. DOI:10.1097/SHK.0000000000000217 · 2.73 Impact Factor
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ABSTRACT: Candida spp. are frequently recovered from endotracheal secretions in critically ill patients suspected of having ventilator-associated pneumonia. Observational studies reported an association with worse clinical outcomes but the effect of antifungal therapy in these patients remains unclear. We designed this pilot study to assess the feasibility of a larger trial and to evaluate inflammatory profiles and clinical outcomes in these patients. We conducted a double-blind, placebo-controlled, multicenter pilot randomized trial of antifungal therapy in critically ill patients with a clinical suspicion of ventilator-associated pneumonia with positive airway secretion specimens for Candida spp. We also included an observational group without Candida spp. in their airway secretions. We measured recruitment rate, inflammatory and innate immune function profiles over time, and clinical outcomes. We recruited 60 patients into the randomized trial and 29 patients into the observational study. Markers of inflammation and all clinical outcomes were comparable between placebo and antifungal treatment group at baseline and over time. At baseline, plasma TNF-alpha levels were higher in patients with VAP and Candida compared to the observational group (mean +/- A SD) (21.8 +/- A 23.1 versus 12.4 +/- A 9.3 pg/ml, p = 0.02) and these patients had lower innate immune function as evidenced by reduced whole blood ex vivo LPS-induced TNF-alpha production capacity (854.8 +/- A 855.2 versus 1,559.4 +/- A 1,290.6 pg/ml, p = 0.01). This study does not provide evidence to support a larger trial examining the efficacy of empiric antifungal treatment in patients with a clinical suspicion of ventilator-associated pneumonia and Candida in the endotracheal secretions. The presence of Candida in the lung may be associated with persistent inflammation and immunosuppression.Intensive Care Medicine 07/2014; 40(9):1313-22. DOI:10.1007/s00134-014-3352-2 · 5.54 Impact Factor