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

Abstract

Thermal injury results in changes in the inflammatory and innate immune response of pediatric patients. Plasma cytokines, cellular profiles, and reduction in innate immune function following burn injury has also been correlated to adverse outcomes (e.g., mortality and infectious complications). Changes in adaptive immune function following thermal injury are not as well characterized. Our goal was to better understand if adaptive immune dysfunction occurs early after pediatric thermal injury and is a risk factor for nosocomial infections (NI). A prospective, longitudinal immune function observational study was performed at a single ABA-verified pediatric burn center. Eighty burn patients were enrolled with 20 developing a NI, defined using CDC criteria. We collected whole blood samples from pediatric burn patients within the first 72 hours from injury and between days 4-7, where applicable to analyze adaptive immune function. We compared immune function between burn patients who went on to develop NI and those that did not. Within the first 72 hours of injury, burn patients who developed NI had significantly lower absolute CD4+ lymphocyte counts and whole blood ex vivo phytohemagglutinin (PHA)-induced IFNγ and IL-10 production capacity compared to those that did not develop infection. Further analysis using receiver operating characteristic curve revealed that PHA-induced IL-10 production capacity had the highest area under the curve. Our data demonstrates early adaptive immune suppression occurs following pediatric thermal injury and PHA-induced IL-10 production capacity appears to be a predictor for the development of NI.

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

“…Advances in the management of these injuries has decreased mortality rates to less than 3%, but infections are still the most common acute complication in patients with significant burn injury ( 24 , 25 ). As the cellular elements of the immune system are essential to defend against these infections, severe abnormalities have been associated with the development of NI ( 7 , 12 , 26 , 27 ). Previous work has identified a number of physiological and metabolic responses to pediatric burn injury and primarily focused on inflammatory responses measuring plasma cytokine profiles ( 6 , 10 , 28 , 29 ).…”

“…( 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 ).…”

“…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.…”

“…Pediatric burn injury has been shown to lead to a dysregulated inflammatory response releasing both pro- (e.g., interleukin (IL)-1, -6) and anti-inflammatory (e.g., IL-4, -10) cytokines, but at differing concentrations than adult burn patients ( 8 – 10 ). The excessive and concurrent release of pro- and anti-inflammatory cytokines (i.e., IL-6, IL-10) that occurs over a short period of time can lead to altered immune function, further resulting in compromised function of multiple organ systems, and ultimately leading to infectious complications or mortality ( 9 – 12 ). Clinicians also face an extreme challenge as this profound inflammatory response that burn patients display closely resembles the excessive and concurrent pro- and anti-inflammatory cytokine release seen in patients who present with infections/sepsis ( 13 ).…”