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 three 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 =0.0015), CD14 + monocyte counts (273 cells/µL vs. 508 cells/µL, p =0.01), and % HLA-DR expression on CD14 + monocytes (54% vs. 92%, p =0.02) compared to 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.

Early detection of soluble CD27, BTLA, and TIM-3 predicts the development of nosocomial infection in pediatric burn patients

“…Typically, after injury there is first a significant release of pro-inflammatory cytokines followed by a delayed anti-inflammatory cytokine response; together they work to counterbalance each other to maintain homeostasis. However, our previous work and this current study show a similar trend to Finnerty et al (10), indicating elevated levels of both pro-inflammatory (IL-6 and IL-8) and anti-inflammatory (IL-10) cytokines within the first couple days after pediatric thermal injury and are further elevated in patients who go on to develop an infection (Figures 1A-C) (7,10,12,32). This dysregulated inflammatory state can alter immune function ultimately leading to infectious complications (10, 12, 32-34).…”

“…Several adult burn studies have pointed to decreased neutrophil and monocyte counts and decreased cellular function after thermal injury (e.g., phagocytosis, bactericidal activity), and has been suggested to be predictors of sepsis (30,(35)(36)(37)(38). We have previously observed similar results to those shown in this study, displaying an inability for those who develop NI to increase their number of absolute CD14+ monocytes unlike those who recovered without an infection (Figure 2E) (7). There was, however, no difference between those who developed a NI and HCs.…”

“…LPS and PHA stimulation solution was manufactured bimonthly in the Immune Surveillance Laboratory at the Research Institute at Nationwide Children’s Hospital and quality controlled to ensure the intra-batch coefficient of variation from healthy donor replicates was <10% for TNFα and IL-10 response, respectively. LPS-stimulated TNFα and PHA-stimulated IL-4, IL-10, and IFNγ were chosen based on our previous studies indicating their prediction of NI in pediatric burn patients ( 7 , 12 ).…”

“…Both innate and adaptive immune cells (e.g., macrophages and lymphocytes, respectively) have shown to be decreased following adult burn injury and further suppressed in those who develop infections ( 6 , 14 ). We have previously shown markers of both innate and adaptive immune function are also decreased in pediatric burn patients who develop infections ( 7 , 12 ). However, there is no standard method to identify those at risk, and the underlying mechanisms and the sequence of events that lead to immunosuppression in burn patients are still largely unknown.…”

“…The American Burn Association states the most clinically relevant complications for pediatric burn patients are pneumonia, urinary tract infection, cellulitis, bacteremia, wound infection, and respiratory failure ( 5 ). In fact, over 60% of patients with large burns will develop an infection ( 6 , 7 ).…”