Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure

Objectives: To test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1 beta levels or interleukin-1 beta response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease. Design: Prospective cohort study. Setting: Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622). Subjects: Children 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease. Measurements and Main Results: Three-hundred seventy-eight of 549 patients had pediatric acute respiratory distress syndrome; DNA and plasma were obtained from 523 of 549 and 480 of 549 patients, respectively. Plasma interleukin-1ra was highest on the day of intubation (day 0) and decreased over the subsequent 3 days (p < 0.0001). Interleukin-1ra level was higher in patients with pediatric acute respiratory distress syndrome than those without pediatric acute respiratory distress syndrome (p < 0.0001). Multivariable regression analysis of data across all days demonstrated a significant association of interleukin-1ra (odds ratio, 1.30; 95% CI, 1.10-1.52; p = 0.002) and day (p < 0.05) with pediatric acute respiratory distress syndrome, independent of age and Pediatric Risk of Mortality-III score. Analysis on individual days indicated that plasma interleukin-1ra levels were associated with pediatric acute respiratory distress syndrome on days 0 and 2, independent of age and Pediatric Risk of Mortality-III score (p = 0.04 and 0.003, respectively), however did not quite reach significance on days 1 and 3 (p = 0.06 and 0.07, respectively). Interleukin-1ra was independently associated with mortality on day 1 (p = 0.02). Interleukin-1ra also correlated with length of mechanical ventilation, measures of oxygenation, and PICU length of stay. No genetic variants were associated with pediatric acute respiratory distress syndrome. Conclusions: Plasma interleukin-1ra is associated with pediatric acute respiratory distress syndrome, PICU length of stay, length of mechanical ventilation, and mortality in children with acute respiratory failure requiring mechanical ventilation.