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Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.

ABSTRACT: OBJECTIVES:To test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1? levels or interleukin-1? response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease. DESIGN:Prospective cohort study. SETTING:Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622). SUBJECTS:Children 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease. MEASUREMENTS AND MAIN RESULTS:Three-hundred seventy-eight of 549 patients had pediatric acute respiratory distress syndrome; DNA and plasma were obtained from 523 of 549 and 480 of 549 patients, respectively. Plasma interleukin-1ra was highest on the day of intubation (day 0) and decreased over the subsequent 3 days (p < 0.0001). Interleukin-1ra level was higher in patients with pediatric acute respiratory distress syndrome than those without pediatric acute respiratory distress syndrome (p < 0.0001). Multivariable regression analysis of data across all days demonstrated a significant association of interleukin-1ra (odds ratio, 1.30; 95% CI, 1.10-1.52; p = 0.002) and day (p < 0.05) with pediatric acute respiratory distress syndrome, independent of age and Pediatric Risk of Mortality-III score. Analysis on individual days indicated that plasma interleukin-1ra levels were associated with pediatric acute respiratory distress syndrome on days 0 and 2, independent of age and Pediatric Risk of Mortality-III score (p = 0.04 and 0.003, respectively), however did not quite reach significance on days 1 and 3 (p = 0.06 and 0.07, respectively). Interleukin-1ra was independently associated with mortality on day 1 (p = 0.02). Interleukin-1ra also correlated with length of mechanical ventilation, measures of oxygenation, and PICU length of stay. No genetic variants were associated with pediatric acute respiratory distress syndrome. CONCLUSIONS:Plasma interleukin-1ra is associated with pediatric acute respiratory distress syndrome, PICU length of stay, length of mechanical ventilation, and mortality in children with acute respiratory failure requiring mechanical ventilation.

SUBMITTER: Dahmer MK

PROVIDER: S-EPMC6170680 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.

Dahmer Mary K MK Quasney Michael W MW Sapru Anil A Gildengorin Ginny G Curley Martha A Q MAQ Matthay Michael A MA Flori Heidi H

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 20181001 10

<h4>Objectives</h4>To test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1β levels or interleukin-1β response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease.<h4>Design</h4>Prospective cohort study.<h4>Setting</h4>Twenty-two PICUs participating in the multisite clinical trial, Randomize ...[more]

PMID: 30095747

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Project description:BackgroundThe association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure.MethodsThis was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped.ResultsFive hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4-12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level.ConclusionsWhen measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.

Project description:OBJECTIVES:Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome. DESIGN:Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children's Hospital of Philadelphia. SETTING:The derivation cohort represented 100 centers worldwide; the validation cohort was from Children's Hospital of Philadelphia. PATIENTS:There were 624 and 640 subjects in the derivation and validation cohorts, respectively. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and PaO2/FIO2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ? 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ? 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts. CONCLUSIONS:We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

Project description:OBJECTIVES:The prevalence and importance of early right ventricular dysfunction and pulmonary hypertension in pediatric acute respiratory distress syndrome are unknown. We aimed to describe the prevalence of right ventricular dysfunction and pulmonary hypertension within 24 hours of pediatric acute respiratory distress syndrome diagnosis and their associations with outcomes. DESIGN:Retrospective, single-center cohort study. SETTING:Tertiary care, university-affiliated PICU. PATIENTS:Children who had echocardiograms performed within 24 hours of pediatric acute respiratory distress syndrome diagnosis. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Between July 1, 2012, and June 30, 2016, 103 children met inclusion criteria. Echocardiograms were analyzed using established indices of right ventricular and left ventricular systolic function and for evidence of pulmonary hypertension. Echocardiographic abnormalities were common: 26% had low right ventricular fractional area change, 65% had low tricuspid annular plane systolic excursion, 30% had low left ventricular fractional shortening, and 21% had evidence of pulmonary hypertension. Abnormal right ventricular global longitudinal strain and abnormal right ventricular free wall strain were present in 35% and 40% of patients, respectively. No echocardiographic variables differed between or across pediatric acute respiratory distress syndrome severity. In multivariable analyses, right ventricular global longitudinal strain was independently associated with PICU mortality (odds ratio, 3.57 [1.33-9.60]; p = 0.01), whereas right ventricular global longitudinal strain, right ventricular free wall strain, and the presence of pulmonary hypertension were independently associated with lower probability of extubation (subdistribution hazard ratio, 0.46 [0.26-0.83], p = 0.01; subdistribution hazard ratio, 0.58 [0.35-0.98], p = 0.04; and subdistribution hazard ratio, 0.49 [0.26-0.92], p = 0.03, respectively). CONCLUSIONS:Early ventricular dysfunction and pulmonary hypertension were detectable, prevalent, and independent of lung injury severity in children with pediatric acute respiratory distress syndrome. Right ventricular dysfunction was associated with PICU mortality, whereas right ventricular dysfunction and pulmonary hypertension were associated with lower probability of extubation.

Project description:Background:Biomarkers are needed for early identification of patients at risk of severe complications from influenza infection, including prolonged respiratory failure and death. Eicosanoids are bioactive lipid mediators with pro- and anti-inflammatory properties produced in response to infection. This study assessed the relationships between the host bioactive lipid response, influenza viral load, and clinical outcomes. Methods:Influenza-positive, intubated children ?18 years old were enrolled across 26 US pediatric intensive care units (PICUs). Mass spectrometry was used to measure >100 lipid metabolites in endotracheal and nasopharyngeal samples. Influenza viral load was measured by quantitative polymerase chain reaction. Results:Age and bacterial co-infection were associated with multiple bioactive lipids (P?<?.05). Influenza viral load was lower in patients with bacterial co-infection compared with those without, and pro-inflammatory bioactive lipids positively correlated with viral load in bacterially co-infected children (P?<?.05). Lipids associated with disease resolution correlated with viral load in patients without bacterial co-infection (P?<?.01). After adjusting for age and bacterial co-infection status, elevated pro- and anti-inflammatory lipids measured early in the intensive care unit course were associated with higher mortality, whereas influenza viral load and endotracheal cytokine levels were not associated with clinical outcomes. Prostaglandin E2, arachidonic acid, docosahexaenoic acid, and 12-hydroxyeicosatetraenoic acid measured within 72 hours of PICU admission predicted death or prolonged (?28 days) mechanical ventilator support (area under the curve, 0.72-0.79; P?<?.02) not explained by admission illness severity. Conclusions:Children with influenza-related complications have early bioactive lipid responses that may reflect lung disease severity. Respiratory bioactive lipids are candidate prognostic biomarkers to identify children with the most severe clinical outcomes.

Project description:Importance: Monocytes are plastic cells that assume different polarization states that can either promote inflammation or tissue repair and inflammation resolution. Polarized monocytes are partially defined by their transcriptional profiles that are influenced by environmental stimuli. The airway monocyte response in pediatric acute respiratory distress syndrome (PARDS) is undefined. Objectives: To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor monocytes exposed to the airway fluid of intubated children with and at-risk for PARDS. To determine differences in gene expression at two time points using the donor monocyte assay exposed to airway fluid from intubated children with PARDS obtained 48-96 hours following initial tracheal aspirate sampling. Design, Setting and Participants: In vitro pilot study carried out using airway fluid supernatant from 57 children: 44 children with PARDS and 13 children at-risk for PARDS. Main Outcomes and Measures: We performed bulk RNA sequencing using a transcriptomic reporter assay of monocytes exposed to airway fluid from intubated children to discover gene networks differentiating PARDS from at-risk for PARDS. We also report differences in gene expression in children with PARDS 48-96 hours following initial tracheal aspirate sampling. Results: We found that interleukin (IL)-10, -4, and -13, cytokine/chemokine signaling, and the senescence-associated secretory phenotype are upregulated in monocytes exposed to airway fluid from intubated children with PARDS compared to those at-risk for PARDS. Signaling by NOTCH, histone deacetylation/acetylation, DNA methylation, chromatin modifications (B-WICH complex), and RNA polymerase I transcription and its associated regulatory apparatus were upregulation in children with PARDS 48-96 hours following initial tracheal aspirate sampling. Conclusions and Relevance: We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a monocyte reporter assay that exposed monocytes to airway fluid from intubated children with and at-risk for PARDS. Mechanistic investigations are needed to validate our findings.

Project description:Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.

Project description:OBJECTIVES:Infectious pneumonia is the most common cause of acute respiratory distress syndrome, with viruses frequently implicated as causative. However, the significance of viruses in pediatric acute respiratory distress syndrome is unknown. We aimed to characterize the epidemiology of viral pneumonia in pediatric acute respiratory distress syndrome and compare characteristics and outcomes between pneumonia subjects with and without viruses. Secondarily, we examined the association between specific viruses and outcomes. DESIGN:We performed a secondary analysis of a prospectively enrolled pediatric acute respiratory distress syndrome cohort. Subjects with pneumonia acute respiratory distress syndrome underwent testing of respiratory secretions for viruses and culture for bacteria and fungi and were stratified according to presence or absence of a virus. SETTING:Tertiary care children's hospital. PATIENTS:Children with acute respiratory distress syndrome. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Of 544 children with acute respiratory distress syndrome, 282 (52%) had pneumonia as their inciting etiology, of whom 212 were virus-positive. In 141 of 282 (50%) pneumonia acute respiratory distress syndrome cases, a virus was the sole pathogen identified. Virus-positive pneumonia had fewer organ failures but worse oxygenation, relative to virus-negative pneumonia, with no differences in antibiotic use, ventilator duration, or mortality. Subjects with respiratory syncytial virus-associated acute respiratory distress syndrome had lower mortality (0%), and subjects with influenza-associated acute respiratory distress syndrome had shorter ventilator duration, relative to other viral acute respiratory distress syndrome. Nonadeno herpesviruses, tested for exclusively in immunocompromised subjects, had greater than 80% mortality. CONCLUSIONS:Pneumonia was the most common cause of pediatric acute respiratory distress syndrome, and viruses were commonly isolated as the sole pathogen. Respiratory syncytial virus and influenza were associated with better outcomes relative to other viral etiologies. Viral pneumonias in immunocompromised subjects, particularly nonadeno herpesviruses, drove the mortality rate for pneumonia acute respiratory distress syndrome. Specific viral etiologies are associated with differential outcomes in pediatric acute respiratory distress syndrome and should be accounted for in future studies.

Project description:OBJECTIVES:To determine whether weight extremes impact clinical outcomes in pediatric acute respiratory distress syndrome. DESIGN:Post hoc analysis of a cohort created by combining five multicenter pediatric acute respiratory distress syndrome studies. SETTING:Forty-three academic PICUs worldwide. PATIENTS:A total of 711 subjects prospectively diagnosed with pediatric acute respiratory distress syndrome. INTERVENTION:Subjects more than 2 years were included and categorized by Center for Disease Control and Prevention body mass index z score criteria: underweight (< -1.89), normal weight (-1.89 to +1.04), overweight (+1.05 to +1.64), and obese (? +1.65). Subjects were stratified by direct versus indirect lung injury leading to pediatric acute respiratory distress syndrome. The primary outcome was in-hospital mortality. In survivors, secondary analyses included duration of mechanical ventilation and ICU length of stay. MEASUREMENTS AND MAIN RESULTS:A total of 331 patients met inclusion criteria; 12% were underweight, 50% normal weight, 11% overweight, and 27% obese. Overall mortality was 20%. By multivariate analysis, body mass index category was independently associated with mortality (p = 0.004). When stratified by lung injury type, there was no mortality difference between body mass index groups with direct lung injury; however, in the indirect lung injury group, the odds of mortality in the obese were significantly lower than normal weight subjects (odds ratio, 0.11; 95% CI, 0.02-0.84). Survivors with direct lung injury had no difference in the duration of mechanical ventilation or ICU length of stay; however, those with indirect lung injury, the overweight required longer duration of mechanical ventilation than other groups (p < 0.001). CONCLUSIONS:These data support the obesity paradox in pediatric acute respiratory distress syndrome. Obese children with indirect lung injury pediatric acute respiratory distress syndrome have a lower risk of mortality. Importantly, among survivors, the overweight with indirect lung injury requires longer duration of mechanical ventilation. Our data require prospective validation to further elucidate the pathobiology of this phenomenon.

Project description:BackgroundCOVID-19's pulmonary manifestations are broad, ranging from pneumonia with no supplemental oxygen requirements to acute respiratory distress syndrome (ARDS) with acute respiratory failure (ARF). In response, new oxygenation strategies and therapeutics have been developed, but their large-scale effects on outcomes in severe COVID-19 patients remain unknown. Therefore, we aimed to examine the trends in mortality, mechanical ventilation, and cost over the first six months of the pandemic for adult COVID-19 patients in the US who developed ARDS or ARF.Methods and findingsThe Vizient Clinical Data Base, a national database comprised of administrative, clinical, and financial data from academic medical centers, was queried for patients ≥ 18-years-old with COVID-19 and either ARDS or ARF admitted between 3/2020-8/2020. Demographics, mechanical ventilation, length of stay, total cost, mortality, and discharge status were collected. Mann-Kendall tests were used to assess for significant monotonic trends in total cost, mechanical ventilation, and mortality over time. Chi-square tests were used to compare mortality rates between March-May and June-August. 110,223 adult patients with COVID-19 ARDS or ARF were identified. Mean length of stay was 12.1±13.3 days and mean total cost was $35,991±32,496. Mechanical ventilation rates were 34.1% and in-hospital mortality was 22.5%. Mean cost trended downward over time (p = 0.02) from $55,275 (March) to $18,211 (August). Mechanical ventilation rates trended down (p<0.01) from 53.8% (March) to 20.3% (August). Overall mortality rates also decreased (p<0.01) from 28.4% (March) to 13.7% (August). Mortality rates in mechanically ventilated patients were similar over time (p = 0.45), but mortality in patients not requiring mechanical ventilation decreased from March-May compared to June-July (13.5% vs 4.6%, p<0.01).ConclusionsThis study describes the outcomes of a large cohort with COVID-19 ARDS or ARF and the subsequent decrease in cost, mechanical ventilation, and mortality over the first 6 months of the pandemic in the US.

Dataset Information

Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.

Publications

Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.

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