BACKGROUNDLower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically ...similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI. Whether it can be applied at scale and in a pediatric population to enable improved diagnosis and treatment remains unclear.METHODSWe used tracheal aspirate RNA-Seq to profile host gene expression and respiratory microbiota in 261 children with acute respiratory failure. We developed a gene expression classifier for LRTI by training on patients with an established diagnosis of LRTI (n = 117) or of noninfectious respiratory failure (n = 50). We then developed a classifier that integrates the host LRTI probability, abundance of respiratory viruses, and dominance in the lung microbiome of bacteria/fungi considered pathogenic by a rules-based algorithm.RESULTSThe host classifier achieved a median AUC of 0.967 by cross-validation, driven by activation markers of T cells, alveolar macrophages, and the interferon response. The integrated classifier achieved a median AUC of 0.986 and increased the confidence of patient classifications. When applied to patients with an uncertain diagnosis (n = 94), the integrated classifier indicated LRTI in 52% of cases and nominated likely causal pathogens in 98% of those.CONCLUSIONLower airway metagenomics enables accurate LRTI diagnosis and pathogen identification in a heterogeneous cohort of critically ill children through integration of host, pathogen, and microbiome features.FUNDINGSupport for this study was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (UG1HD083171, 1R01HL124103, UG1HD049983, UG01HD049934, UG1HD083170, UG1HD050096, UG1HD63108, UG1HD083116, UG1HD083166, UG1HD049981, K23HL138461, and 5R01HL155418) as well as by the Chan Zuckerberg Biohub.
Eph/Ephrin Signaling in Injury and Inflammation Coulthard, Mark G; Morgan, Michael; Woodruff, Trent M ...
The American journal of pathology,
11/2012, Letnik:
181, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The Eph/ephrin receptor–ligand system plays an important role in embryogenesis and adult life, principally by influencing cell behavior through signaling pathways, resulting in modification of the ...cell cytoskeleton and cell adhesion. There are 10 EphA receptors, and six EphB receptors, distinguished on sequence difference and binding preferences, that interact with the six glycosylphosphatidylinositol-linked ephrin-A ligands and the three transmembrane ephrin-B ligands, respectively. The Eph/ephrin proteins, originally described as developmental regulators that are expressed at low levels postembryonically, are re-expressed after injury to the optic nerve, spinal cord, and brain in fish, amphibians, rodents, and humans. In rodent spinal cord injury, the up-regulation of EphA4 prevents recovery by inhibiting axons from crossing the injury site. Eph/ephrin proteins may be partly responsible for the phenotypic changes to the vascular endothelium in inflammation, which allows fluid and inflammatory cells to pass from the vascular space into the interstitial tissues. Specifically, EphA2/ephrin-A1 signaling in the lung may be responsible for pulmonary inflammation in acute lung injury. A role in T-cell maturation and chronic inflammation (heart failure, inflammatory bowel disease, and rheumatoid arthritis) is also reported. Although there remains much to learn about Eph/ephrin signaling in human disease, and specifically in injury and inflammation, this area of research raises the exciting prospect that novel therapies will be developed that precisely target these pathways.
Acute respiratory distress syndrome is a heterogeneous pathophysiological process responsible for significant morbidity and mortality in pediatric intensive care patients. Diagnosis is defined by ...clinical characteristics that identify the syndrome after development. Subphenotyping patients at risk of progression to ARDS could provide the opportunity for therapeutic intervention. microRNAs, non-coding RNAs stable in circulation, are a promising biomarker candidate. We conducted a single-center prospective cohort study to evaluate random forest classification of microarray-quantified circulating microRNAs in critically ill pediatric patients. We additionally selected a sub-cohort for parallel metabolomics profiling as a pilot study for concurrent use of miRNAs and metabolites as circulating biomarkers. In 35 patients (n = 21 acute respiratory distress, n = 14 control) 15 microRNAs were differentially expressed. Unsupervised random forest classification accurately grouped ARDS and control patients with an area under the curve of 0.762, which was improved to 0.839 when subset to only patients with bacterial infection. Nine metabolites were differentially abundant between acute respiratory distress and control patients (n = 4, both groups) and abundance was highly correlated with miRNA expression. Random forest classification of microRNAs differentiated critically ill pediatric patients who developed acute respiratory distress relative to those who do not. The differential expression of microRNAs and metabolites provides a strong foundation for further work to validate their use as a prognostic biomarker.
In this issue of the Journal, Barbaro and colleagues (pp. 1177- 1186) begin to shed more light on the role of ECMO in pediatric acute respiratory distress syndrome (ARDS) (6). Using existing data ...collected from the multicenter RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) randomized controlled trial (7), the authors examined the effect of ECMO on mortality, ventilator-free and hospital days, and cerebral functional status at hospital discharge. ECMO-supported patients who developed severe ARDS also had a higher admission risk of mortality, a higher number of organ system failures, and higher use of high-frequency oscillation ventilation than non-ECMO-supported patients who developed severe ARDS. ...with only 61 ECMO-supported patients, the study was not sufficiently powered to detect small differences in mortality that might be considered clinically significant. ...we agree with Barbaro and colleagues that a rigorously performed randomized controlled clinical trial of ECMO in severe pediatric ARDS should be performed, but the results they report suggest that such a trial is likely infeasible.
OBJECTIVES:The objective of this study was to compare survival outcomes and intra-arrest arterial blood pressures between children receiving cardiopulmonary resuscitation for bradycardia and poor ...perfusion and those with pulseless cardiac arrests.
DESIGN:Prospective, multicenter observational study.
SETTING:PICUs and cardiac ICUs of the Collaborative Pediatric Critical Care Research Network.
PATIENTS:Children (< 19 yr old) who received greater than or equal to 1 minute of cardiopulmonary resuscitation with invasive arterial blood pressure monitoring in place.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Of 164 patients, 96 (59%) had bradycardia and poor perfusion as the initial cardiopulmonary resuscitation rhythm. Compared to those with initial pulseless rhythms, these children were younger (0.4 vs 1.4 yr; p = 0.005) and more likely to have a respiratory etiology of arrest (p < 0.001). Children with bradycardia and poor perfusion were more likely to survive to hospital discharge (adjusted odds ratio, 2.31; 95% CI, 1.10–4.83; p = 0.025) and survive with favorable neurologic outcome (adjusted odds ratio, 2.21; 95% CI, 1.04–4.67; p = 0.036). There were no differences in diastolic or systolic blood pressures or event survival (return of spontaneous circulation or return of circulation via extracorporeal cardiopulmonary resuscitation). Among patients with bradycardia and poor perfusion, 49 of 96 (51%) had subsequent pulselessness during the cardiopulmonary resuscitation event. During cardiopulmonary resuscitation, these patients had lower diastolic blood pressure (point estimate, –6.68 mm Hg –10.92 to –2.44 mm Hg; p = 0.003) and systolic blood pressure (point estimate, –12.36 mm Hg –23.52 to –1.21 mm Hg; p = 0.032) and lower rates of return of spontaneous circulation (26/49 vs 42/47; p < 0.001) than those who were never pulseless.
CONCLUSIONS:Most children receiving cardiopulmonary resuscitation in ICUs had an initial rhythm of bradycardia and poor perfusion. They were more likely to survive to hospital discharge and survive with favorable neurologic outcomes than patients with pulseless arrests, although there were no differences in immediate event outcomes or intra-arrest hemodynamics. Patients who progressed to pulselessness after cardiopulmonary resuscitation initiation had lower intra-arrest hemodynamics and worse event outcomes than those who were never pulseless.
Stimulation by the ephrin-A1 ligand of the EphA2 receptor increases endothelial permeability. Lung injury increases the expression of EphA2, but the role of EphA2 in such injury is not well ...understood. To determine whether EphA2 contributes to changes in permeability and inflammation in the injured lung, we studied wild-type (WT) and EphA2 knockout (KO) mice, using isolated, perfused lung (IPL) preparations and a model of bleomycin-induced lung injury. We also studied the response of endothelial cells to ephrin-A1. In the IPL preparations, ephrin-A1 increased the filtration coefficient in WT mice, but not in EphA2 KO mice, demonstrating that EphA2 regulates vascular permeability. In early bleomycin injury in WT mice, the expression of both EphA2 and ephrin-A1 increased. EphA2 KO animals were protected from lung injury, showing less water and alveolar protein in the lungs than WT mice, consistent with reduced permeability. Bleomycin caused less accumulation of lung leukocytes in EphA2 KO animals than in WT animals, suggesting that EphA2 regulates inflammation. To determine whether EphA2 deficiency alters the production of chemokines, CXCL1 and CCL2 in the lungs were measured. After bleomycin injury, EphA2 KO animals produced less CXCL1 and CCL2 than WT animals. Because NF-κβ mediates the production of chemokines, the effect of the ephrin-A1 ligand on the activation of NF-κβ and the expression of chemokines was measured in endothelial cells. Ephrin-a1 significantly increased NF-κβ nuclear translocation and the expression of chemokine mRNA. This study demonstrates that the expression of EphA2 increases in the injured lung, and not only contributes to changes in permeability, but also plays a previously unrecognized role in promoting inflammatory responses.
To characterize the impact of public health interventions on the volume and characteristics of admissions to the PICU.
Multicenter retrospective cohort study.
Six U.S. referral PICUs during February ...15, 2020-May 14, 2020, compared with the same months during 2017-2019 (baseline).
PICU admissions excluding admissions for illnesses due to severe acute respiratory syndrome coronavirus 2 and readmissions during the same hospitalization.
None.
Primary outcome was admission volumes during the period of stay-at-home orders (March 15, 2020-May 14, 2020) compared with baseline. Secondary outcomes were hospitalization characteristics including advanced support (e.g., invasive mechanical ventilation), PICU and hospital lengths of stay, and mortality. We used generalized linear mixed modeling to compare patient and admission characteristics during the stay-at-home orders period to baseline. We evaluated 7,960 admissions including 1,327 during March 15, 2020-May 14, 2020. Daily admissions and patients days were lower during the period of stay-at-home orders compared with baseline: median admissions 21 (interquartile range, 17-25) versus 36 (interquartile range, 30-42) (p < 0.001) and median patient days 93.0 (interquartile range, 55.9-136.7) versus 143.6 (interquartile range, 108.5-189.2) (p < 0.001). Admissions during the period of stay-at-home orders were less common in young children and for respiratory and infectious illnesses and more common for poisonings, endocrinopathies and for children with race/ethnicity categorized as other/unspecified. There were no differences in hospitalization characteristics except fewer patients received noninvasive ventilation during the period of stay-at-home orders.
Reductions in PICU admissions suggest that much of pediatric critical illness in younger children and for respiratory and infectious illnesses may be preventable through targeted public health strategies.
IMPORTANCE: Approximately 40% of children who experience an in-hospital cardiac arrest survive to hospital discharge. Achieving threshold intra-arrest diastolic blood pressure (BP) targets during ...cardiopulmonary resuscitation (CPR) and systolic BP targets after the return of circulation may be associated with improved outcomes. OBJECTIVE: To evaluate the effectiveness of a bundled intervention comprising physiologically focused CPR training at the point of care and structured clinical event debriefings. DESIGN, SETTING, AND PARTICIPANTS: A parallel, hybrid stepped-wedge, cluster randomized trial (Improving Outcomes from Pediatric Cardiac Arrest—the ICU-Resuscitation Project ICU-RESUS) involving 18 pediatric intensive care units (ICUs) from 10 clinical sites in the US. In this hybrid trial, 2 clinical sites were randomized to remain in the intervention group and 2 in the control group for the duration of the study, and 6 were randomized to transition from the control condition to the intervention in a stepped-wedge fashion. The index (first) CPR events of 1129 pediatric ICU patients were included between October 1, 2016, and March 31, 2021, and were followed up to hospital discharge (final follow-up was April 30, 2021). INTERVENTION: During the intervention period (n = 526 patients), a 2-part ICU resuscitation quality improvement bundle was implemented, consisting of CPR training at the point of care on a manikin (48 trainings/unit per month) and structured physiologically focused debriefings of cardiac arrest events (1 debriefing/unit per month). The control period (n = 548 patients) consisted of usual pediatric ICU management of cardiac arrest. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to hospital discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1 to 3 or no change from baseline (score range, 1 normal to 6 brain death or death). The secondary outcome was survival to hospital discharge. RESULTS: Among 1389 cardiac arrests experienced by 1276 patients, 1129 index CPR events (median patient age, 0.6 IQR, 0.2-3.8 years; 499 girls 44%) were included and 1074 were analyzed in the primary analysis. There was no significant difference in the primary outcome of survival to hospital discharge with favorable neurologic outcomes in the intervention group (53.8%) vs control (52.4%); risk difference (RD), 3.2% (95% CI, −4.6% to 11.4%); adjusted OR, 1.08 (95% CI, 0.76 to 1.53). There was also no significant difference in survival to hospital discharge in the intervention group (58.0%) vs control group (56.8%); RD, 1.6% (95% CI, −6.2% to 9.7%); adjusted OR, 1.03 (95% CI, 0.73 to 1.47). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial conducted in 18 pediatric intensive care units, a bundled intervention of cardiopulmonary resuscitation training at the point of care and physiologically focused structured debriefing, compared with usual care, did not significantly improve patient survival to hospital discharge with favorable neurologic outcome among pediatric patients who experienced cardiac arrest in the ICU. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02837497
To identify postdischarge outcome phenotypes and risk factors for poor outcomes using insurance claims data.
Retrospective cohort study.
Single quaternary center.
Children without preexisting ...tracheostomy who required greater than or equal to 3 days of invasive mechanical ventilation, survived the hospitalization, and had postdischarge insurance eligibility in Colorado's All Payer Claims Database.
None.
We used unsupervised machine learning to identify functional outcome phenotypes based on claims data representative of postdischarge morbidities. We assessed health trajectory by comparing change in the number of insurance claims between quarters 1 and 4 of the postdischarge year. Regression analyses identified variables associated with unfavorable outcomes. The 381 subjects had median age 3.3 years (interquartile range, 0.9-12 yr), and 147 (39%) had a complex chronic condition. Primary diagnoses were respiratory (41%), injury (23%), and neurologic (11%). We identified three phenotypes: lower morbidity (n = 300), higher morbidity (n = 62), and 1-year nonsurvivors (n = 19). Complex chronic conditions most strongly predicted the nonsurvivor phenotype. Longer PICU stays and tracheostomy placement most strongly predicted the higher morbidity phenotype. Patients with high but improving postdischarge resource use were differentiated by high illness severity and long PICU stays. Patients with persistently high or increasing resource use were differentiated by complex chronic conditions and tracheostomy placement.
New morbidities are common after prolonged mechanical ventilation. Identifying phenotypes at high risk of postdischarge morbidity may facilitate prognostic enrichment in clinical trials.
Objective:
Establish the feasibility of pediatric intensive care unit (PICU) nurse-directed ultrasound assessment (UA) of peripheral intravenous (PIV) catheters, compare the results of UA to ...traditional assessment (TA), and determine PIV survival after UA.
Design:
Prospective observational cohort study.
Setting:
PICU within a children’s hospital.
Patients:
PICU patients with a PIV.
Interventions:
None.
Measurements and main results:
Eight nurses performed UA on 131 PIVs in 85 patients. Median age was 3.0 years (IQR 1.0–13.8) and median weight was 15.0 kg (IQR 9.6–59.3). The most common PIV location was the arm (43%) and extravasation occurred in 15% of PIVs. Agreement between TA and UA was moderate with a Kappa of 0.47 (95% CI 0.28–0.66). Nursing confidence in the UA was significantly higher than TA (92% vs 21% very confident, p < 0.0001). In 106 PIVs with a UA that indicated the PIV was intravascular (i.e. negative UA), the median survival was 50.0 h (IQR 21.8–100.3).
Conclusions:
Nurses can perform UA of PIV status in PICU patients and express greater confidence in the findings of UA than TA. Further study is necessary to determine the impact of UA on the rate of PIV complications.
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