Innate Immune Function Predicts the Development of Nosocomial Infection in Critically Injured Children

Abstract

Background Critical injury has been associated with reduction in innate immune function in adults, with infection risk being related to degree of immune suppression. This relationship has not been reported in critically injured children. Hypothesis Innate immune function will be reduced in critically injured children, and the degree of reduction will predict the subsequent development of nosocomial infection. Materials and Methods Children (≤ 18 years of age) were enrolled in this longitudinal, prospective, observational, single-center study after admission to the pediatric intensive care unit (PICU) following critical injury, along with a cohort of outpatient controls. Serial blood sampling was performed to evaluate plasma cytokine levels and innate immune function as measured by ex vivo LPS-induced TNFα production capacity. Results Seventy-six critically injured children (and 21 outpatient controls) were enrolled. Sixteen critically injured subjects developed nosocomial infection. Those subjects had higher plasma IL-6 and IL-10 levels on post-trauma day (PTD) 1–2 compared to those who recovered without infection and outpatient controls. Ex vivo LPS-induced TNFα production capacity was lower in children on PTD 1–2 (p=0.006) and over the first week following injury (p=0.04) in those who went on to develop infection. A TNFα response of < 520 pg/ml at any time in the first week after injury was highly associated with infection risk by univariate and multivariate analysis. Among transfused children, longer red blood cell storage age, not transfusion volume, was associated with lower innate immune function (p < 0.0001). Trauma-induced innate immune suppression was reversible ex vivo via co-culture of whole blood with GM-CSF. Conclusions Trauma-induced innate immune suppression is common in critically injured children and is associated with increased risks for the development of nosocomial infection. Potential exacerbating factors, including red blood cell transfusion, and potential therapies for pediatric trauma-induced innate immune suppression are deserving of further study.

Critical Illness–Induced Immune Suppression: Current State of the Science

“…Indeed, reduced whole blood ex vivo lipopolysaccharide-induced tumor necrosis factor (TNF)-α production capacity has been associated with increased risks for secondary infection and death in sepsis, critical viral infections, trauma, and cardiopulmonary bypass. 4,7,11,37,38 …”

“…4,11,23 In the case of traumatic injury, the severity of the initial injury is often associated with the development of impaired immune function in the ICU. 5,24 Moreover, certain types of injury are prone to greater degrees of immune suppression.…”

“…Critical illness-induced immune suppression has been demonstrated in children and adults with a variety of diagnoses, including trauma, 4,5 sepsis, [6][7][8] pancreatitis, 9,10 severe viral infections, 11,12 and following cardiopulmonary bypass. 13,14 The clinical consequences of immune suppression in the ICU setting include increased risk of multiple organ dysfunction syndrome, 15 increased susceptibility to secondary bacterial infections, 4,7,16 reactivation of latent viruses, 17 susceptibility to opportunistic organisms, 18,19 and increased risk of death.…”

“…13,14 The clinical consequences of immune suppression in the ICU setting include increased risk of multiple organ dysfunction syndrome, 15 increased susceptibility to secondary bacterial infections, 4,7,16 reactivation of latent viruses, 17 susceptibility to opportunistic organisms, 18,19 and increased risk of death. 6,7,20 Now that most critically ill patients are surviving the acute phase of their illness as the result of advances in supportive care, many patients are facing the subacute or chronic phases of their illness bearing the additional burden of secondary immune suppression.…”

Immunoparalysis in Pediatric Critical Care

“…The largest body of evidence in critically ill children associating low innate immune function with adverse outcomes, spanning multiple diagnostic groups, uses this method of immune function testing. 11, 15–18 …”