Innate Immune Function and Mortality in Critically Ill Children With Influenza: A Multicenter Study*

Hall MW, Geyer SM, Guo CY, Panoskaltsis-Mortari A, Jouvet P, Ferdinands J, Shay DK, Nateri J, Greathouse K, Sullivan R, Tran T, Keisling S, Randolph AG; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators.

Collaborators (35)

Source

1 Department of Pediatrics, Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH. 2 The Research Institute at Nationwide Children's Hospital, Columbus, OH. 3 Division of Hematology, The Ohio State University College of Medicine, Columbus, OH. 4 Institute of Public Health, National Yang Ming University, Taiwan, Republic of China. 5 Department of Pediatrics, Bone Marrow Transplantation, Pulmonary & Critical Care Medicine, University of Minnesota, Minneapolis, MN. 6 Saint Justine's Children's Hospital, Montreal, Quebec, Canada. 7 Division of Influenza, Centers for Disease Control and Prevention, Atlanta, GA. 8 Harvard Medical School, Boston, MA. 9 Department of Anesthesia, Perioperative, and Pain Medicine, Boston Children's Hospital, Boston, MA. 10 Clinical Research Program, Boston Children's Hospital, Boston, MA. Dr. Randolph is the senior author on this article.

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 0.0001="" and="" associated="" aureus="" both="" can="" children.="" children="" coexist="" coinfection="" conclusions::="" critical="" cytokines="" death="" degree="" demonstrated="" duration="" early="" feasible="" function="" greatest="" high-risk="" high="" highly="" icu="" identify="" immune="" immunosuppression="" in="" influenza.="" innate="" is="" levels="" longer="" marked="" ml="" mortality="" multicenter="" of="" p="" patients="" pg="" population.="" predictive="" s.="" serum="" severe="" stay="" suppression="" testing="" the="" these="" this="" was="" with="">