PURPOSE OF THE STUDY.
The influenza virus can inhibit leukocyte function in vitro and in vivo, and is associated with severe secondary bacterial infections. Immunoparalysis is the state marked by reduction in the ability to produce tumor necrosis factor (TNF)-α in response to lipopolysaccharide (LPS). This study sought to test the hypothesis that mortality from influenza in critically ill children and young adults is associated with both hypercytokinemia and innate immune suppression.
Patients <18 years old, who were admitted to 1 of the 15 PICUs that belong to the Pediatric Acute Lung Injury and Sepsis Investigators network, with community-acquired influenza infection, from December 2008 to November 2009 were included. A control group of outpatient children who presented for elective phlebotomy was also evaluated.
Serum samples were assayed for 31 cytokine levels and ex vivo LPS-stimulated TNF-α production capacity by using a standardized stimulation protocol. Levels were drawn within 72 hours of ICU admission.
Fifty-two subjects and 21 controls were sampled. There were 8 deaths among the subjects. Nonsurvivors had significantly lower counts of neutrophils, monocytes, and lymphocytes, and more frequent secondary bacterial infection than survivors. Six mediators (granulocyte macrophage colony–stimulating factor, interleukin-6, interleukin-8, interferon-inducible protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α) were significantly higher among nonsurvivors compared with survivors and controls. ICU patients had significantly lower TNF-α production in response to LPS compared with controls. Nonsurvivors also had lower TNF-α production compared with survivors. Lower TNF-α production was also associated with more days in the ICU. The most common influenza subtype was 2009 H1N1, which was associated with lower TNF-α production compared with other influenza strains. Staphylococcus aureus, the most common bacterial co-infection, was associated with lower TNF-α production compared with other bacterial co-infection or no co-infection.
Children with critical influenza can have marked innate immune suppression, which can co-exist with high serum cytokine levels. Severe innate immune suppression is highly associated with mortality and S aureus co-infection.
This is the first multicenter evaluation of the relationships between innate immune function, serum cytokines/chemokines, and outcomes in children with critical illness resulting from influenza. Despite elevated levels of proinflammatory cytokines/chemokines, innate immune function was suppressed. The hypercytokinemia echoes studies of adult influenza nonsurvivors. The study shows the feasibility of large-scale immune monitoring among multiple centers. Of note, the subjects were sampled at only 1 time point. In addition, the severe leukopenia could have contributed to the immunoparalysis. Interestingly, 2009 H1N1 influenza has been linked to a more robust cytokine response to other influenza subtypes. Larger studies will be needed to assess factors such as age, race, location, and other co-morbidities. Research should also target improving innate immune function during critical influenza illness.
- Copyright © 2013 by the American Academy of Pediatrics