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Objective Extreme preterm infants are a growing population in neonatal intensive care units who carry a high mortality and morbidity. Multiple factors play a role in preterm birth, resulting in major impact on organogenesis leading to complications including bronchopulmonary dysplasia (BPD). The goal of this study was to identify biomarker signatures associated with prematurity and BPD. Study design We analyzed miRNA and mRNA profiles in tracheal aspirates (TAs) from 55 infants receiving invasive mechanical ventilation. Twenty-eight infants were extremely preterm and diagnosed with BPD, and 27 were term babies receiving invasive mechanical ventilation for elective procedures. Result We found 22 miRNAs and 33 genes differentially expressed (FDR Conclusions Specific mRNA-miRNA signatures in TAs may serve as biomarkers for BPD pathogenesis, a consequence of extreme prematurity.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth, arrested fetal lung development, and inflammation. The incidence of BPD remains on the rise as a result of increasing survival of extremely preterm infants. Severe BPD contributes to significant health care costs and is associated with prolonged hospitalizations, respiratory infections, and neurodevelopmental deficits. In this study, we aimed to detect novel biomarkers of BPD severity. We collected tracheal aspirates (TAs) from preterm babies with mild/moderate (n = 8) and severe (n = 17) BPD, and we profiled the expression of 1048 miRNAs using a PCR array. Associations with biological pathways were determined with the Ingenuity Pathway Analysis (IPA) software. We found 31 miRNAs differentially expressed between the two disease groups (2-fold change, false discovery rate (FDR) &lt, 0.05). Of these, 4 miRNAs displayed significantly higher expression levels, and 27 miRNAs had significantly lower expression levels in the severe BPD group when compared to the mild/moderate BPD group. IPA identified cell signaling and inflammation pathways associated with miRNA signatures. We conclude that TAs of extremely premature infants contain miRNA signatures associated with severe BPD. These may serve as potential biomarkers of disease severity in infants with BPD.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth and arrested fetal lung development. The incidence of BPD remains on the rise, as a result of increasing survival of extremely preterm infants. Severe BPD contributes to significant health care costs and is associated with prolonged hospitalizations, respiratory infections, and neurodevelopmental deficits. In this study, we aimed to detect novel biomarkers of severe BPD. We collected tracheal aspirates (TA) from preterm babies with mild/moderate (n = 8) and severe (n = 17) BPD, and we profiled the expression of 1048 miRNAs using a PCR array. Associations with biological pathways were determined with the Ingenuity Pathway Analysis (IPA) software. We found 31 miRNAs differentially expressed between the two disease groups (2-fold change, FDR < 0.05). Of these, 4 miRNAs displayed significantly higher expression levels, and 27 miRNAs had significantly lower expression levels in the severe BPD vs. the mild/moderate BPD group. IPA identified cell signaling and inflammation pathways associated with miRNA signatures. We conclude that TAs of extreme premature infants contain miRNA signatures associated with severe BPD. These signatures may serve as biomarkers of disease severity in infants with BPD.

BACKGROUND: Decreased tumor necrosis factor (TNF)-α production in whole blood following ex vivo lipopolysaccharide (LPS) stimulation indicates suppression of the toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether anti-viral immune signaling pathways are also suppressed in these patients is unclear. OBJECTIVES: We sought to evaluate suppression of the TLR4 and the anti-viral retinoic acid-inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection. METHODS: In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand, polyinosinic-polycytidylic acid (poly(I:C))-low molecular weight/LyoVec™ and LPS to evaluate interferon (IFN)-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively). RESULTS: Suppression of either IFNα or TNFα production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n=33/103, 32%) were more likely to have prolonged (≥7 days) multiple organ dysfunction syndrome (30.3% vs 8.6%, p=0.004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4% p=0.001) compared to those with single- or no pathway suppression. CONCLUSIONS: Suppression of both RIG-I and TLR4 signaling pathways, essential for respective anti-viral and anti-bacterial pathogens responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial co-infection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring.

Rationale Effective immunomodulatory therapies for children with life-threatening “cytokine storm” triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis. Objectives To compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications. Methods Children with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO. Measurements and main results Modules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p

Background Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza severity in adults. IFITM3 has not been evaluated in pediatric influenza. Methods The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA. Results In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the Δ21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified. Conclusions rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.

Objective: There is a paucity of literature evaluating the effects of family member presence during bedside medical rounds in the pediatric intensive care unit. We hypothesized that, when compared with rounds without family members, parental presence during morning medical rounds would increase time spent on rounds, decrease medical team teaching/education, increase staff dissatisfaction, create more stress in family members, and violate patient privacy in our open unit. Design: Prospective, blinded, observational study. Setting: Academic pediatric intensive care unit with 12 beds. Participants: A total of 105 admissions were studied, 81 family members completed a survey, and 187 medical team staff surveys were completed. Interventions: Investigators documented parental presence and time allocated for presentation, teaching, and answering questions. Surveys related to perception of goals, teaching, and privacy of rounds were distributed to participants. Measurements: Time spent on rounds, time spent teaching on rounds, and medical staff and family perception of the effects of parental presence on rounds. Results: There was no significant difference between time spent on rounds in the presence or absence of family members (p = NS). There is no significant difference between the time spent teaching by the attending physician in the presence or absence of family members (p = NS). Overall, parents reported that the medical team spent an appropriate amount of time discussing their child and were not upset by this discussion. Parents did not perceive that their own or their child's privacy was violated during rounds. The majority of medical team members reported that the presence of family on rounds was beneficial. Conclusions: Parental presence on rounds does not seem to interfere with the educational and communication process. Parents report satisfaction with participation in rounds, and privacy violations do not seem to be a concern from their perspective.