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Innate immune function and mortality in critically ill children with influenza: a multicenter study
Mark W Hall1, Susan M Geyer, Chao-Yu Guo
1Department of Pediatrics, Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA. Mark.Hall@NationwideChildrens.org
Insights
Critically ill children with influenza and high cytokine levels often have immune suppression, increasing mortality risk. Early immune suppression, especially with Staphylococcus aureus coinfection, predicts death in pediatric influenza patients.
Area of Science:
- Pediatric critical care medicine
- Immunology
- Infectious diseases
Background:
- Influenza infection in children can lead to critical illness.
- Understanding the immune response is crucial for predicting outcomes.
Purpose of the Study:
- To investigate the link between serum cytokine levels, immune function, and mortality in critically ill children with influenza.
- To assess the feasibility of multicenter innate immune function testing.
Main Methods:
- A prospective, multicenter observational study involving 15 pediatric ICUs.
- Measured serum cytokine levels and ex vivo tumor necrosis factor-α production in 52 critically ill children and 21 controls.
- Assessed secondary infections, particularly Staphylococcus aureus.
Main Results:
- High serum cytokine levels (e.g., IL-6, TNF-α) and Staphylococcus aureus coinfection were associated with increased mortality.
- Nonsurvivors exhibited immunosuppression with reduced tumor necrosis factor-α production capacity.
- Low tumor necrosis factor-α response (<250 pg/mL) predicted death and longer ICU stays.
Conclusions:
- Critical influenza in children can present with both high cytokines and immune suppression.
- Early, severe innate immune suppression is linked to Staphylococcus aureus coinfection and mortality.
- Multicenter immune function testing can identify high-risk pediatric patients.
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.
