Bria M. Coates

Influence of definition and location of hypotension on outcome following severe pediatric traumatic brain injury

Objective:To examine the influence of definition and location (field, emergency department, or pediatric intensive care unit) of hypotension on outcome following severe pediatric traumatic brain injury. Design:Retrospective cohort study. Setting:Harborview Medical Center (level I pediatric trauma center), Seattle, WA, over a 5-yr period between 1998 and 2003. Patients:Ninety-three children <14 yrs of age with traumatic brain injury following injury, head Abbreviated Injury Score ≥3, and pediatric intensive care unit admission Glasgow Coma Scale score <9 formed the analytic sample. Data sources included the Harborview Trauma Registry and hospital records. Interventions:None. Measurements and Main Results:The relationship between hypotension and outcome was examined comparing two definitions of hypotension: a) systolic blood pressure <5th percentile for age; and b) systolic blood pressure <90 mm Hg. Hospital discharge Glasgow Outcome Score <4 or disposition of either death or discharge to a skilled nursing facility was considered a poor outcome. Pediatric intensive care unit and hospital length of stay were also examined. Systolic blood pressure <5th percentile for age was more highly associated with poor hospital discharge Glasgow Outcome Score (p = .001), poor disposition (p = .02), pediatric intensive care unit length of stay (rate ratio 9.5; 95% confidence interval 6.7–12.3), and hospital length of stay (rate ratio 18.8; 95% confidence interval 14.0–23.5) than systolic blood pressure <90 mm Hg. Hypotension occurring in either the field or emergency department, but not in the pediatric intensive care unit, was associated with poor Glasgow Outcome Score (p = .008), poor disposition (p = .03), and hospital length of stay (rate ratio 18.7; 95% confidence interval 13.1–24.2). Conclusions:Early hypotension, defined as systolic blood pressure <5th percentile for age in the field and/or emergency department, was a better predictor of poor outcome than delayed hypotension or the use of systolic blood pressure <90 mm Hg.

Molecular mechanisms of host cell invasion by Trypanosoma cruzi.

The protozoan parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, is an obligate intracellular protozoan pathogen. Overlapping mechanisms ensure successful infection, yet the relationship between these cellular events and clinical disease remains obscure. This review explores the process of cell invasion from the perspective of cell surface interactions, intracellular signaling, modulation of the host cytoskeleton and endosomal compartment, and the intracellular innate immune response to infection.

Influenza A Virus Infection, Innate Immunity, and Childhood

Infection with influenza A virus is responsible for considerable morbidity and mortality in children worldwide. While it is apparent that adequate activation of the innate immune system is essential for pathogen clearance and host survival, an excessive inflammatory response to infection is detrimental to the young host. A review of the literature indicates that innate immune responses change throughout childhood. Whether these changes are genetically programmed or triggered by environmental cues is unknown. The objectives of this review are to summarize the role of innate immunity in influenza A virus infection in the young child and to highlight possible differences between children and adults that may make children more susceptible to severe influenza A infection. A better understanding of age-related differences in innate immune signaling will be essential to improve care for this high-risk population.

Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection

Influenza A virus (IAV) is a significant cause of life-threatening lower respiratory tract infections in children. Antiviral therapy is the mainstay of treatment, but its effectiveness in this age group has been questioned. In addition, damage inflicted on the lungs by the immune response to the virus may be as important to the development of severe lung injury during IAV infection as the cytotoxic effects of the virus itself. A crucial step in the immune response to IAV is activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the subsequent secretion of the inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). The IAV matrix 2 proton channel (M2) has been shown to be an important activator of the NLRP3 inflammasome during IAV infection. We sought to interrupt this ion channel-mediated activation of the NLRP3 inflammasome through inhibition of NLRP3 or the cytokine downstream from its activation, IL-1β. Using our juvenile mouse model of IAV infection, we show that inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, beginning 3 days after infection with IAV, improves survival in juvenile mice. Treatment with MCC950 reduces NLRP3 levels in lung homogenates, decreases IL-18 secretion into the alveolar space, and inhibits NLRP3 inflammasome activation in alveolar macrophages. Importantly, inhibition of the NLRP3 inflammasome with MCC950 does not impair viral clearance. In contrast, inhibition of IL-1β signaling with the IL-1 receptor antagonist, anakinra, is insufficient to protect juvenile mice from IAV. Our findings suggest that targeting the NLRP3 inflammasome in juvenile IAV infection may improve disease outcomes in this age group.

Performance of capnometry in non-intubated infants in the pediatric intensive care unit

BackgroundAssessing the ventilatory status of non-intubated infants in the Pediatric Intensive Care Unit (PICU) is a constant challenge. Methods to evaluate ventilation include arterial blood gas analysis (ABG), which is invasive and intermittent, and transcutaneous carbon dioxide monitoring (PtcCO2), which, while non-invasive, is also intermittent. A method that is non-invasive and continuous would be of great benefit in this population. We hypothesized that non-invasive capnometry via sidestream monitoring of exhaled carbon dioxide (CO2) would provide an acceptable measurement of ventilatory status when compared to ABG or PtcCO2.MethodsPreliminary prospective study of infants less than one year of age admitted to the PICU in a large urban teaching hospital. Infants not intubated and not requiring non-invasive ventilation were eligible. A sidestream CO2 reading was obtained in a convenience sample of 39 patients. A simultaneous ABG was collected in those with an arterial catheter, and a PtcCO2 was obtained in those without.ResultsCorrelation of sidestream CO2 with ABG was excellent (r2 = 0.907). Sidestream correlated less well with PtcCO2 (r2 = 0.649). Results were not significantly altered when weight and respiratory rate were added as independent variables. Bland-Altman analysis revealed a bias of -2.7 with a precision of ±6.5 when comparing sidestream CO2 to ABG, and a bias of -1.7 with a precision of ±9.9 when comparing sidestream CO2 to PtcCO2.ConclusionsPerformance of sidestream monitoring of exhaled CO2 is acceptable clinical trending to assess the effectiveness of ventilation in non-intubated infants in the PICU.

Inflammatory Monocytes Drive Influenza A Virus–Mediated Lung Injury in Juvenile Mice

Healthy children are more likely to die of influenza A virus (IAV) infection than healthy adults. However, little is known about the mechanisms underlying the impact of young age on the development of life-threatening IAV infection. We report increased mortality in juvenile mice compared with adult mice at each infectious dose of IAV. Juvenile mice had sustained elevation of type I IFNs and persistent NLRP3 inflammasome activation in the lungs, both of which were independent of viral titer. Juvenile mice, but not adult mice, had increased MCP-1 levels that remained high even after viral clearance. Importantly, continued production of MCP-1 was associated with persistent recruitment of monocytes to the lungs and prolonged elevation of inflammatory cytokines. Transcriptional signatures of recruited monocytes to the juvenile and adult IAV-infected lungs were assessed by RNA-seq. Genes associated with a proinflammatory signature were upregulated in the juvenile monocytes compared with adult monocytes. Depletion of monocytes with anti-CCR2 Ab decreased type I IFN secretion, NLRP3 inflammasome activation, and lung injury in juvenile mice. This suggests an exaggerated inflammatory response mediated by increased recruitment of monocytes to the lung, and not an inability to control viral replication, is responsible for severe IAV infection in juvenile mice. This study provides insight into severe IAV infection in juveniles and identifies key inflammatory monocytes that may be central to pediatric acute lung injury secondary to IAV.

Endothelial transmigration by Trypanosoma cruzi.

Chagas heart disease, the leading cause of heart failure in Latin America, results from infection with the parasite Trypanosoma cruzi. Although T. cruzi disseminates intravascularly, how the parasite contends with the endothelial barrier to escape the bloodstream and infect tissues has not been described. Understanding the interaction between T. cruzi and the vascular endothelium, likely a key step in parasite dissemination, could inform future therapies to interrupt disease pathogenesis. We adapted systems useful in the study of leukocyte transmigration to investigate both the occurrence of parasite transmigration and its determinants in vitro. Here we provide the first evidence that T. cruzi can rapidly migrate across endothelial cells by a mechanism that is distinct from productive infection and does not disrupt monolayer integrity or alter permeability. Our results show that this process is facilitated by a known modulator of cellular infection and vascular permeability, bradykinin, and can be augmented by the chemokine CCL2. These represent novel findings in our understanding of parasite dissemination, and may help identify new therapeutic strategies to limit the dissemination of the parasite.

The Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Pulmonary Infection

&NA; Pneumonia is caused by both viral and bacterial pathogens and is responsible for a significant health burden in the Unites States. The innate immune system is the human bodys first line of defense against these pathogens. The recognition of invading pathogens via pattern recognition receptors leads to proinflammatory cytokine and chemokine production, followed by recruitment and activation of effector immune cells. The nonspecific inflammatory nature of the innate immune response can result in immunopathology that is detrimental to the host. In this review, we focus on one class of pattern recognition receptors, the nucleotide‐binding oligomerization domain (NOD)‐like receptors, specifically NOD1 and NOD2, and their role in host defense against viral and bacterial pathogens of the lung, including influenza, respiratory syncytial virus, Streptococcus pneumoniae, Chlamydophila pneumoniae, and Staphylococcus aureus. It is hoped that improved understanding of NOD1 and NOD2 activity in pneumonia will facilitate the development of novel therapies and promote improved patient outcomes.

654: INHIBITION OF THE NLRP3 INFLAMMASOME PROTECTS JUVENILE MICE FROM LETHAL IAV INFECTION

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) parapsilosis isolates underwent molecular typing using a panel of 5 multilocus microsatellite markers. The C. parapsilosis isolates were genotyped using a published microsatellite type protocol. The C. pelliculosa isolates were genotyped using newly developed multilocus sequence typing of 5 different genes. Chart reviews were done on all patients admitted to the relevant unit within 6 days of each case’s infection date. The proportions of select medications during the same time period were compared between the 5 cases and the remaining patient pool. Results: Four cases occurred within 56 day period. The fifth case occurred 203 days after the fourth case. Two cases died. All 5 cases were admitted in the intensive care unit (ICU) (1 in the neonatal ICU and 4 in the pediatric ICU). Three cases were male and the median age was 293 days (range 10-369 days). Total Parenteral Nutrition (TPN) use was significantly higher in cases (5/5; 100%) when compared with controls (52/164; 31.7%); this difference was statistically significant (p=.004). The results of the genotyping data for the 3 C. parapsilosis isolates and the 5 C. pelliculosa isolates showed that the isolates from the patients were identical to one another and different from unrelated control isolates, suggesting a clonal origin. Conclusions: The genotyping analysis of the C. parapsilosis and C. pelliculosa isolates confirmed identity of the strains and suggested an outbreak. TPN use was a risk factor and a possible source of infection. Environmental cultures may aid in identification of the point source. To our knowledge, this is the first reported outbreak of C. pelliculosa.