Jennifer A. Muszynski

Immunosuppressive effects of red blood cells on monocytes are related to both storage time and storage solution

BACKGROUND: Reduced monocyte function is associated with adverse outcomes from critical illness. Red blood cells (RBCs) are thought to impair monocyte function but relationships between RBC storage solution and monocyte suppression are unknown. This study was designed to test the hypothesis that immunosuppressive effects of RBCs on monocytes are related to both storage time and preservative solution.

Timing of correct parenteral antibiotic initiation and outcomes from severe bacterial community-acquired pneumonia in children.

Background: The impact of timing of appropriate antibiotic initiation for critically ill children with severe bacterial community-acquired pneumonia (CAP) is unknown. We hypothesized that longer time to initiation of correct parenteral antibiotic would be associated with longer durations of mechanical ventilation, intensive care unit length of stay, and hospital length of stay. Methods: We retrospectively reviewed medical records of children admitted to Nationwide Childrens Hospital between January 2004 and December 2006 with bacterial CAP treated with mechanical ventilation, excluding those with documented viral infection. Time to correct antibiotic was defined as time from presentation to any emergency department to the initiation of a parenteral antibiotic to which cultured pathogens were susceptible. Results: In all, 45 patients, median age 17 months, were identified. Median time to correct antibiotic was 10.3 hours, with 71% of patients receiving correct empiric therapy. After adjusting for severity of illness, longer time to correct antibiotic was independently associated with longer hospital stay (P = 0.007). For the 23 patients in the cohort for whom pneumonia was the primary diagnosis, longer time to correct antibiotic was independently associated with longer durations of mechanical ventilation (P = 0.01), intensive care unit stay (P = 0.001), and hospital stay (P = 0.006). Delays in antibiotic administration as short as 2 to 4 hours were associated with adverse outcomes in this group. Conclusions: In our critically ill children with severe bacterial CAP, longer delays in receipt of appropriate empiric antibiotics were independently associated with adverse outcomes.

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. Methods: Children (⩽18 years old) were enrolled in this longitudinal, prospective, observational, single-center study after admission to the pediatric intensive care unit 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 lipopolysaccharide-induced tumor necrosis factor &agr; (TNF-&agr;) 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 interleukin 6 and interleukin 10 levels on posttrauma days 1–2 compared with those who recovered without infection and outpatient controls. Ex vivo lipopolysaccharide-induced TNF-&agr; production capacity was lower on posttrauma days 1–2 (P = 0.006) and over the first week following injury (P = 0.04) in those who went on to develop infection. A TNF-&agr; response of less than 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 coculture of whole blood with granulocyte-macrophage colony-stimulating factor. 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.

Transfusion‐related immunomodulation: review of the literature and implications for pediatric critical illness

Transfusion‐related immunomodulation (TRIM) in the intensive care unit (ICU) is difficult to define and likely represents a complicated set of physiologic responses to transfusion, including both proinflammatory and immunosuppressive effects. Similarly, the immunologic response to critical illness in both adults and children is highly complex and is characterized by both acute inflammation and acquired immune suppression. How transfusion may contribute to or perpetuate these phenotypes in the ICU is poorly understood, despite the fact that transfusion is common in critically ill patients. Both hyperinflammation and severe immune suppression are associated with poor outcomes from critical illness, underscoring the need to understand potential immunologic consequences of blood product transfusion. In this review we outline the dynamic immunologic response to critical illness, provide clinical evidence in support of immunomodulatory effects of blood product transfusion, review preclinical and translational studies to date of TRIM, and provide insight into future research directions.

Supernatants from stored red blood cell (RBC) units, but not RBC-derived microvesicles, suppress monocyte function in vitro.

We have previously shown that critically ill children transfused with red blood cells (RBCs) of longer storage durations have more suppressed monocyte function after transfusion compared to children transfused with fresher RBCs and that older stored RBCs directly suppress monocyte function in vitro, through unknown mechanisms. We hypothesized that RBC‐derived microvesicles (MVs) were responsible for monocyte suppression.

Multidisciplinary quality improvement initiative to reduce ventilator-associated tracheobronchitis in the PICU.

Objective: To test the hypothesis that successful implementation of a care bundle designed to prevent nosocomial airway infection will be associated with decreased incidence of ventilator-associated tracheobronchitis. Design: Prospective pre- and postinterventional. Setting: PICU at an academic medical center Patients: All patients admitted to the PICU who received invasive mechanical ventilation for greater than or equal to 48 hours between March 1, 2009, and December 31, 2011. Intervention: Multidisciplinary, unitwide implementation of an evidence-based care bundle to prevent ventilator-associated airway infection. Measurements and Main Results: There were 725 patients included in the analysis (338 patients preintervention and 387 patients postintervention). Baseline ventilator-associated tracheobronchitis rate in the preintervention period was 3.9 cases per 1,000 ventilator days compared with 1.8 cases per 1,000 ventilator days postintervention (p = 0.04, Fisher exact test). Compared with patients without ventilator-associated tracheobronchitis or ventilator-associated pneumonia, patients with ventilator-associated tracheobronchitis had fewer ventilator-free days in 28 days (4.9 vs 22; p < 0.0001, Mann-Whitney U test) and fewer ICU-free days in 28 days (0.5 vs 19; p < 0.0001, Mann-Whitney U test). These relationships remained significant after adjusting for covariates by multivariable linear regression. Conclusions: Successful implementation of a care bundle to prevent ventilator-associated infection was associated with decreased incidence of ventilator-associated tracheobronchitis. Development of ventilator-associated tracheobronchitis was independently associated with adverse outcomes in our cohort of pediatric ICU patients.

Red blood cell transfusion and immune function in critically ill children: a prospective observational study

Our previous in vitro work showed that stored red blood cells (RBCs) increasingly suppress markers of innate immune function with increased storage time. This multicenter prospective observational study tests the hypothesis that a single RBC transfusion in critically ill children is associated with immune suppression as a function of storage time.

Immune modulation in sepsis

The vast majority of morbidity and mortality from sepsis can be attributed to the host immune response to infection rather than the infection itself. The innate and adaptive immune systems both contribute to this process. Numerous therapies aimed at reducing the pro-inflammatory burden of acute sepsis have been studied in clinical trials, with most producing disappointing results. The inflammatory response to sepsis has since been shown to be highly dynamic, with a period of compensatory down- regulation of the pro-inflammatory response dominating in the subacute phase of illness. This state, when prolonged and severe, is termed immunoparalysis and is associated with increased risks for nosocomial infection and death. Early evidence suggests that this state may be reversible with beneficial effects on outcomes. Other strategies for manipulating the inflammatory response in the setting of sepsis include the use of corticosteroids, immunonutrition, extracorporeal therapies, intravenous immunoglobulin, and the modulation of pre-existing immunosuppressive drugs. Clinical trials investigating immune modulation in sepsis have largely been done without the benefit of prospective immune monitoring and have rarely been done in children. Immune phenotype-directed therapies aimed at restoring immunologic homeostasis in pediatric sepsis represent the next step on the path toward improving sepsis outcomes in children.

Inflammation and innate immune function in critical illness.

Purpose of review The purpose of review is to highlight the inflammatory response in critical illness and the importance of immune monitoring and modulation in the diagnosis and treatment of critical illness-induced innate immune suppression. Recent findings The pro and anti-inflammatory responses are known to be concurrently activated in many patients requiring intensive care, with innate immune suppression emerging as an important, and potentially reversible, complication of critical illness. Summary The initial inflammatory response to critical illness is typically driven by innate immune cells, including neutrophils, monocytes, and macrophages. The proinflammatory mediators made by these cells are responsible for many of the pathophysiologic features of critical illness. Concurrent with this, however, is a compensatory anti-inflammatory response, including the elaboration of anti-inflammatory mediators and impairment of innate immune cell function. This includes reduction of monocyte human leukocyte antigen-DR expression and impairment of the ability of innate immune cells to produce tumor necrosis factor alpha when stimulated ex vivo. In its most severe form this is referred to as immunoparalysis, and is associated with markedly increased risks for secondary infection and death in the ICU. Prospective testing can detect this phenomenon, and immunostimulatory strategies, including the use of granulocyte macrophage-colony stimulating factor, have the potential to restore innate immune function in this setting.

Sepsis-induced Innate and Adaptive Immune Suppression

The inflammatory response to sepsis has classically been characterized by an overactive innate immune response. Recent adult and pediatric evidence suggests that the immune response is quite dynamic in this setting, often with endogenous innate and adaptive immunosuppression following the onset of sepsis. Sepsis-induced innate immune dysfunction can include reduction in antigen presenting capacity (as evidenced by decreased monocyte HLA-DR expression) and low pro-inflammatory cytokine production capacity (as evidenced by reduced ex vivo LPS-induced tumor necrosis factor-� production). The term immunoparalysis describes a state of severe reduction in these parameters and has been associated with increased risks for the development of nosocomial infection and death in septic adults and children. Intriguing evidence suggests that immunoparalysis may be reversible with beneficial effects on outcomes. Adaptive immune dysfunction has also been reported following the onset of sepsis. Lymphopenia, lymphocyte apoptosis, and skewing toward anti-inflammatory T cell subtypes (such as regulatory T cells) have all been associated with adverse outcomes from sepsis. Without specific testing, most aspects of sepsis-related immune dysfunction are occult. Accordingly, the development of robust immune monitoring and modulation protocols should be a high priority in the battle to improve outcomes from sepsis in critically ill adults and children.