Measures of Systemic Innate Immune Function Predict the Risk of Nosocomial Infection in Pediatric Burn Patients

Abstract

Critical injury-induced immune suppression has been associated with adverse outcomes. This acquired form of immunosuppression is poorly understood in pediatric burn patients, who have infectious complication rates as high as 71%. Our primary objectives were to determine if thermal injury results in early innate immune dysfunction and is associated with increased risk for nosocomial infections (NI). We performed a prospective, longitudinal immune function observational study at a single pediatric burn center. Whole blood samples from burn patients within the first week of injury were used to assess innate immune function. Nosocomial infections were defined using CDC criteria. Immune parameters were compared between patients who went on to develop NI and those that did not. We enrolled a total of 34 patients with 12 developing a NI. Within the first 3 days of injury, children whom developed NI had significantly lower whole blood ex vivo LPS-induced TNFα production capacity (434 pg/mL vs 960 pg/mL, P = .0015), CD14+ monocyte counts (273 cells/µL vs 508 cells/µL, P = .01), and % HLA-DR expression on CD14+ monocytes (54% vs 92%, P = .02) compared with those that did not develop infection. Plasma cytokine levels did not have a significant difference between the NI and no NI groups. Early innate immune suppression can occur following pediatric thermal injury and appears to be a risk factor for the development of nosocomial infections. Plasma cytokines alone may not be a reliable predictor of the development of NI.

Figure 1.

Innate immune function within the first 72 h following pediatric thermal injury. Circulating absolute CD14⁺ monocyte counts (A), CD14+ monocyte HLA-DR expression (B), and ex vivo LPS-induced TNFα production capacity (C) were all significantly lower in children that went on to develop nosocomial infection (NI, n = 12) compared to those patients that did not (No NI, n = 22). All samples from children with thermal injury were obtained within 72 h after injury. For subjects with multiple samples during that time frame, the lowest value was used in the analyses. Data from age-matched healthy control subjects (HC, n = 11) showed higher CD14+ monocyte HLA-DR expression and TNFα production capacity compared to subjects in the NI group, though HC had similar absolute CD14+ monocyte counts, suggesting a failure to increase CD14+ cells after injury in the NI group. Statistical analysis was performed using one-way ANOVA plus Dunn’s test. Lines and boxes represent median and interquartile range; whiskers represent the range throughout.

Figure 2.

Innate immune function over the first week following pediatric thermal injury. Among subjects sampled on Day 0 to 3 and Day 4 to 7 after thermal injury, ex vivo LPS-induced TNFα production capacity (A) and CD14+ monocyte HLA-DR expression (B) were lower over the first week following thermal injury in subjects who went on to develop nosocomial infection (NI, solid squares, n = 9) compared subjects that did not develop NI (No NI, solid circles, n = 8). Statistical analysis was performed using two-way ANOVA. Symbols represent median values while error bars represent interquartile ranges.

Figure 3.

Plasma cytokine levels within the first 72 h following pediatric thermal injury. Plasma levels of IL-2 (A), IL-6 (B), IL-8 (C), IL-10 (D), IL-12 (E), and IL-17 (F) were similar between thermally injured subjects who went on to develop nosocomial infection (NI, n = 12) and those who did not (No NI, n = 22) in the first 72 h after injury. Subjects who went on to develop NI, however, had higher plasma levels of IL-6, IL-8, and IL-10 compared to healthy controls (HC, n = 11). Statistical analysis was performed using one-way ANOVA plus Dunn’s test. Lines and boxes represent median and interquartile range; whiskers represent the range throughout.

Figure 4.

Receiver operating characteristic curve analysis within the first 72 h of pediatric thermal injury of innate immune function compared to plasma cytokine levels of IL-6 and IL-8. The ROC curves demonstrate early markers of innate immune function (TNFα production capacity and %HLA-DR) are better able to determine the risk of subsequent nosocomial infection as compared to plasma levels of the cytokines IL-6 and IL-8.