Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort.

Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

A Targeted Analysis of Serial Cytokine Measures and Nonpulmonary Organ System Failure in Children With Acute Respiratory Failure: Individual Measures and Trajectories Over Time.

OBJECTIVES: There is a need for research exploring the temporal trends of nonpulmonary organ dysfunction (NPOD) and biomarkers in order to identify unique predictive or prognostic phenotypes. We examined the associations between the number and trajectories of NPODs and plasma biomarkers of early and late inflammatory cascade activation, specifically plasma interleukin-1 receptor antagonist (IL-1ra) and interleukin-8 (IL-8), respectively, in the setting of acute respiratory failure (ARF). DESIGN: Secondary analysis of the Randomized Evaluation for Sedation Titration for Respiratory Failure clinical trial and Biomarkers in Acute Lung Injury (BALI) ancillary study. SETTING: Multicenter. PATIENTS: Intubated pediatric patients with ARF. INTERVENTIONS: NPODs were evaluated against plasma IL-1ra and IL-8 levels on individual days (1 to 4 d after intubation) and longitudinally across days. MEASUREMENTS AND MAIN RESULTS: Within the BALI cohort, 432 patients had at least one value for IL-1ra or IL-8 within days 0 through 5. 36.6% had a primary diagnosis of pneumonia, 18.5% had a primary diagnosis of sepsis and 8.1% died. Multivariable logistic regression models showed that increasing levels of both plasma IL-1ra and IL-8 were statistically significantly associated with increasing numbers of NPODs (IL-1ra: days 1-3; IL-8: days 1-4), independent of sepsis diagnosis, severity of oxygenation defect, age, and race/ethnicity. Longitudinal trajectory analysis identified four distinct NPOD trajectories and seven distinct plasma IL-1ra and IL-8 trajectories. Multivariable ordinal logistic regression revealed that specific IL-1ra and IL-8 trajectory groups were associated with greater NPOD trajectory group ( p = 0.004 and p < 0.0001, respectively), independent of severity of oxygenation defect, age, sepsis diagnosis, and race/ethnicity. CONCLUSIONS: Both the inflammatory biomarkers and number of NPODs exhibit distinct trajectories over time with strong associations with one another. These biomarkers and their trajectory patterns may be useful in evaluating the severity of multiple organ dysfunction syndrome in critically ill children and identifying those phenotypes with time-sensitive, treatable traits.

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2).

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

Pathobiology, Severity, and Risk Stratification of Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: To review the literature for studies published in children on the pathobiology, severity, and risk stratification of pediatric acute respiratory distress syndrome (PARDS) with the intent of guiding current medical practice and identifying important areas for future research related to severity and risk stratification. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from 2013 to March 2022 by using a combination of medical subject heading terms and text words to capture the pathobiology, severity, and comorbidities of PARDS. STUDY SELECTION: We included studies of critically ill patients with PARDS that related to the severity and risk stratification of PARDS using characteristics other than the oxygenation defect. Studies using animal models, adult only, and studies with 10 or fewer children were excluded from our review. DATA EXTRACTION: Title/abstract review, full-text review, and data extraction using a standardized data collection form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize relevant evidence and develop recommendations for clinical practice. There were 192 studies identified for full-text extraction to address the relevant Patient/Intervention/Comparator/Outcome questions. One clinical recommendation was generated related to the use of dead space fraction for risk stratification. In addition, six research statements were generated about the impact of age on acute respiratory distress syndrome pathobiology and outcomes, addressing PARDS heterogeneity using biomarkers to identify subphenotypes and endotypes, and use of standardized ventilator, physiologic, and nonpulmonary organ failure measurements for future research. CONCLUSIONS: Based on an extensive literature review, we propose clinical management and research recommendations related to characterization and risk stratification of PARDS severity.

NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications.

BACKGROUND: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. OBJECTIVE: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. METHODS: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control. RESULTS: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. CONCLUSIONS: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.

Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndrome.

Paediatric acute respiratory distress syndrome (PARDS) is a heterogeneous clinical syndrome that is associated with high rates of mortality and long-term morbidity. Factors that distinguish PARDS from adult acute respiratory distress syndrome (ARDS) include changes in developmental stage and lung maturation with age, precipitating factors, and comorbidities. No specific treatment is available for PARDS and management is largely supportive, but methods to identify patients who would benefit from specific ventilation strategies or ancillary treatments, such as prone positioning, are needed. Understanding of the clinical and biological heterogeneity of PARDS, and of differences in clinical features and clinical course, pathobiology, response to treatment, and outcomes between PARDS and adult ARDS, will be key to the development of novel preventive and therapeutic strategies and a precision medicine approach to care. Studies in which clinical, biomarker, and transcriptomic data, as well as informatics, are used to unpack the biological and phenotypic heterogeneity of PARDS, and implementation of methods to better identify patients with PARDS, including methods to rapidly identify subphenotypes and endotypes at the point of care, will drive progress on the path to precision medicine.

Analysis of inflammatory cytokines in the chest tube drainage of post-operative superior cavopulmonary connection patients.

INTRODUCTION: Prolonged pleural effusions are common post Fontan operation and are associated with morbidity. Fontan pleural effusions have elevated proinflammatory cytokines. Little is known about the chest tube drainage after a superior cavopulmonary connection. We examined the chest tube drainage and the inflammatory profiles in post-operative superior cavopulmonary connection patients. METHODS: This prospective cohort study enrolled 25 patients undergoing superior cavopulmonary connection and 10 age-similar controls. Data are also compared to 25 previously published Fontan patients and their 15 age-similar controls. Chest tube samples were analysed with a 17-cytokine BioPlex Assay. Descriptive statistics and univariate comparisons were made between groups. RESULTS: Duration of chest tube drainage was significantly shorter in superior cavopulmonary connection patients (median 4 days, [interquartile range 3-5 days]) versus Fontan patients (10 days, [7-11 days], p < 0.0001). Cytokine concentrations were higher on post-operative day 1 in superior cavopulmonary connection patients versus Fontan patients (all p ≤ 0.01), however levels were comparable to age-similar controls. While proinflammatory IL 8, MIP-1ß, and TNF-α concentrations increased in chest tube drainage of Fontan patients from post-operative day 1 to last chest tube day (all p < 0.0001), there was no change in these biomarkers in superior cavopulmonary connection patients, their controls, or Fontan controls. CONCLUSIONS: Our study demonstrates that after superior cavopulmonary connection, proinflammatory cytokines in the chest tube drainage remain similar to biventricular controls of both age groups, unlike the significant rise over time observed in Fontan patients. Inflammation within the chest tube drainage is likely not innate to single ventricle patients.

Clinical Outcomes of Acute Respiratory Failure Associated With Noninvasive and Invasive Ventilation in a Pediatric ICU.

BACKGROUND: It remains unknown if pediatric patients failing initial noninvasive ventilation (NIV) experience worse clinical outcomes than those successfully treated with NIV or those primarily intubated. METHODS: This was a single-center, retrospective review of patients admitted with acute respiratory failure to the University of Michigan pediatric intensive care or cardiothoracic ICUs and receiving NIV or invasive mechanical ventilation as first-line therapy. RESULTS: One hundred seventy subjects met inclusion criteria and were enrolled: 65 NIV success, 55 NIV failure, and 50 invasive mechanical ventilation alone. Of those failing NIV, median time to intubation was 1.8 (interquartile range [IQR] < 1-7) h. On multivariable regression, ICU-free days were significantly different between groups (NIV success: 22.9 ± 6.9 d; NIV failure: 13.0 ± 6.6 d; invasive ventilation: 12.5 ± 6.9 d; P < .001 across all groups). Multivariable regression revealed no difference in ventilator-free days between NIV failure and invasive ventilation groups (15.4 ± 10.1 d vs 15.9 ± 9.7 d, P = .71). Of 64 subjects (37.6%) meeting Pediatric Acute Lung Injury Consensus Conference pediatric ARDS criteria, only 14% were successfully treated with NIV. Ventilator-free days were similar between the NIV failure and invasive ventilation groups (11.6 vs 13.2 d, P = .47). On multivariable analysis, ICU-free days were significantly different across pediatric ARDS groups (P < .001): NIV success: 20.8 + 31.7 d; NIV failure: 8.3 + 23.8 d; invasive alone: 8.9 + 23.9 d, yet no significant difference in ventilator-free days between those with NIV failure versus invasive alone (11.6 vs 13.2 d, P = .47). CONCLUSIONS: We demonstrated that critically ill pediatric subjects unsuccessfully trialed on NIV did not experience increased ICU length of stay or fewer ventilator-free days when compared to those on invasive mechanical ventilation alone, including in the pediatric ARDS subgroup. Our findings are predicated on a median time to intubation of < 2 h in the NIV failure group and the provision of adequate monitoring while on NIV.

Differences in the Genomic Profiles of Immunoparalyzed and Nonimmunoparalyzed Children With Sepsis: A Pilot Study.

OBJECTIVES: Sepsis-induced immunoparalysis represents a pathologic downregulation of leukocyte function shown to be associated with adverse outcomes, although its mechanisms remain poorly understood. Our goal was to compare genome-wide gene expression profiles of immunoparalyzed and nonimmunoparalyzed children with sepsis to identify genes and pathways associated with immunoparalysis. DESIGN: Prospective observational study. PATIENTS: Twenty-six children with lower respiratory tract infection meeting criteria for sepsis, severe sepsis, or septic shock admitted to the PICU. SETTING: Two tertiary care PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Innate immune function was assayed ex vivo by measuring release of tumor necrosis factor-α from whole blood after incubation with lipopolysaccharide for 4 hours. Immunoparalysis was defined as a tumor necrosis factor-α production capacity less than 200 pg/mL. Ten of the 26 children were immunoparalyzed. There were 17 significant differentially expressed genes when comparing genome-wide gene expression profiles of immunoparalyzed and nonimmunoparalyzed children (false discovery rate < 0.05). Nine genes showed increased expression in immunoparalyzed children (+1.5- to +8.8-fold change). Several of these dampen the immune system. Eight showed decreased expression in immunoparalyzed children (-1.7- to -3.9-fold change), several of which are involved in early regulation and activation of immune function. Functional annotation clustering using differentially expressed genes with p value of less than 0.05 showed three clusters related to immunity with significant enrichment scores (2.2-4.5); the most significant gene ontology terms in these clusters were antigen processing and presentation and negative regulation of interleukin-6 production. Network analysis identified potential protein interactions that may be involved in the development of immunoparalysis in children. CONCLUSIONS: In this exploratory analysis, immunoparalyzed children with sepsis showed increased expression of genes that dampen the immune system and decreased expression of genes involved in regulation and activation of the immune system. Analysis also implicated other proteins as potentially having as yet unidentified roles in the development of immunoparalysis.

Patterns of Delirium in a Pediatric Intensive Care Unit and Associations With Noise Pollution.

Objective: Delirium is a common problem in the Pediatric Intensive Care Unit (PICU) and is associated with increased length of stay, cost and mortality. This study evaluated the relationship between noise pollution and delirium risk. Design: This is a Quality Improvement (QI) initiative at an academic PICU. Sound levels were monitored and patients were screened for delirium using the Cornell Assessment of Pediatric Delirium (CAPD). Setting PICU Patients: All PICU patients Interventions: None Measurements and Main Results: Over the 83-week study period (2015-2017), the median [IQR] CAPD score was 8 [3 to 14]. Nursing compliance with the CAPD was 72.2%. The proportion of patients screening positive for delirium (CAPD ≥ 9) was 45.9%. A total of 329 711 hly decibel (dB) measurements were collected and reported. Occupied rooms were louder than unoccupied rooms (51.8 [51.6-51.9] dB vs. 49.8 [49.7-49.9] dB, respectively, p < 0.001). Days (10 AM to 4 PM) were louder than nights (11 PM to 5 AM) (52.8 [52.7-53.0] dB vs. 50.7 [49.9-51.5] dB, respectively p < 0.001) in occupied rooms. Winter (Nov-Feb) months were louder than summer (May-Aug) months (52.0 [51.8-52.3] dB vs. 51.5 [51.3-51.7] dB, respectively, p < 0.002) in occupied rooms. Median weekly nighttime noise levels and CAPD scores demonstrated a correlation coefficient of 0.6 (p < 0.001). Median weekly risk of mortality (ROM) and CAPD scores demonstrated a correlation coefficient of 0.15 (p < 0.01). Conclusions: Significant noise pollution exists in the PICU with a moderate correlation between nighttime noise levels and CAPD scores. This could potentially implicate noise pollution as a risk factor for the development of delirium.

Identification of phenotypes in paediatric patients with acute respiratory distress syndrome: a latent class analysis.

BACKGROUND: Previous latent class analysis of adults with acute respiratory distress syndrome (ARDS) identified two phenotypes, distinguished by the degree of inflammation. We aimed to identify phenotypes in children with ARDS in whom developmental differences might be important, using a latent class analysis approach similar to that used in adults. METHODS: This study was a secondary analysis of data aggregated from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial and the Genetic Variation and Biomarkers in Children with Acute Lung Injury (BALI) ancillary study. We used latent class analysis, which included demographic, clinical, and plasma biomarker variables, to identify paediatric ARDS (PARDS) phenotypes within a cohort of children included in the RESTORE and BALI studies. The association of phenotypes with clinically relevant outcomes and the performance of paediatric data in adult ARDS classification algorithms were also assessed. FINDINGS: 304 children with PARDS were included in this secondary analysis. Using latent class analysis, a two-class model was a better fit for the cohort than a one-class model (p<0·001). Latent class analysis identified two classes: class 1 (181 [60%] of 304 patients with PARDS) and class 2 (123 [40%] of 304 patients with PARDS), referred to as phenotype 1 and 2 hereafter. Phenotype 2 was characterised by higher concentrations of inflammatory biomarkers, a higher incidence of vasopressor use, and more frequent diagnosis of sepsis, consistent with the adult hyperinflammatory phenotype. All levels of severity of PARDS were observed across both phenotypes. Children with the hyperinflammatory phenotype (phenotype 2) had worse clinical outcomes than those with the hypoinflammatory phenotype (phenotype 1), with a longer duration of mechanical ventilation (median 10·0 days [IQR 6·3-21·0] for phenotype 2 vs 6·6 days [4·1-10·8] for phenotype 1, p<0·0001), and higher incidence of mortality (17 [13·8%] of 123 patients vs four [2·2%] of 181 patients, p=0·0001). When using adult phenotype classification algorithms in children, the soluble tumour necrosis factor receptor-1 (sTNFr1), vasopressor use, and interleukin (IL)-6 variables gave an area under the curve (AUC) of 0·956, and the sTNFr1, vasopressor use, and IL-8 variables gave an AUC of 0·954, compared with the gold standard of latent class analysis. INTERPRETATION: Latent class analysis identified two phenotypes in children with ARDS with characteristics similar to those in adults, including worse outcomes among patients with the hyperinflammatory phenotype. PARDS phenotypes should be considered in design and analysis of future clinical trials in children. FUNDING: US National Institutes of Health.

Epidemiology and Outcomes of Critically Ill Children at Risk for Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017). SETTING: Thirty-seven international PICUs. PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:Fio2 ratio, progressive tachycardia, and early diuretic administration. CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

Thrombomodulin is associated with increased mortality and organ failure in mechanically ventilated children with acute respiratory failure: biomarker analysis from a multicenter randomized controlled trial.

BACKGROUND: Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. METHODS: This was a prospective observational study of 432 patients aged 2 weeks-17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. RESULTS: sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n = 432, adjusted HR = 1.003, p = 0.02) and worse OI in the first 5 days after intubation (n = 252, Estimate = 0.02, p < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p < 0.0001; and slope, Estimate = 0.01, p = 0.0009, n = 386). CONCLUSIONS: Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.

Inflammatory Biomarkers Are Associated With a Decline in Functional Status at Discharge in Children With Acute Respiratory Failure: An Exploratory Analysis.

To evaluate the link between early acute respiratory failure and functional morbidity in survivors using the plasma biomarkers interleukin-8, interleukin-1 receptor antagonist, thrombomodulin, and plasminogen activator inhibitor-1. We hypothesized that children with acute respiratory failure with higher levels of inflammation would have worse functional outcomes at discharge, as measured by Pediatric Overall Performance Category. DESIGN: Secondary analysis of the Genetic Variation and Biomarkers in Children with Acute Lung Injury (R01HL095410) study. SETTING: Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622) and the ancillary study (Biomarkers in Children with Acute Lung Injury). SUBJECTS: Children 2 weeks to 17 years requiring invasive mechanical ventilation for acute airways and/or parenchymal lung disease. Patients with an admission Pediatric Overall Performance Category greater than 3 (severe disability, coma, or brain death) were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among survivors, 387 patients had no worsening of Pediatric Overall Performance Category at discharge while 40 had worsening functional status, defined as any increase in Pediatric Overall Performance Category from baseline. There was no significant relationship between worsening of Pediatric Overall Performance Category and interleukin-8 or plasminogen activator inhibitor-1 on any day. There was no significant relationship between interleukin-1 receptor antagonist, or thrombomodulin, and worsening Pediatric Overall Performance Category on day 1. Plasma interleukin-1 receptor antagonist and thrombomodulin were significantly elevated on days 2 and 3 in those with worse functional status at discharge compared with those without. In multivariable analysis, interleukin-1 receptor antagonist and thrombomodulin were associated with a decline in functional status on days 2 and 3 after adjustment for age and highest oxygenation index. However, after adjusting for age and cardiovascular failure, only day 2 thrombomodulin levels were associated with a worsening in Pediatric Overall Performance Category. CONCLUSIONS: Higher levels of interleukin-1 receptor antagonist or thrombomodulin following intubation were associated with worse Pediatric Overall Performance Category scores at hospital discharge in children who survive acute respiratory failure. These data suggest that persistent inflammation may be related to functional decline.

Association of patient weight status with plasma surfactant protein D, a biomarker of alveolar epithelial injury, in children with acute respiratory failure.

AIMS AND OBJECTIVES: Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission. METHODS: Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested. RESULTS: Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05). CONCLUSIONS: Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.

The common K333Q polymorphism in long-chain acyl-CoA dehydrogenase (LCAD) reduces enzyme stability and function.

The fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD) is expressed at high levels in human alveolar type II (ATII) cells in the lung. A common polymorphism causing an amino acid substitution (K333Q) was previously linked to a loss of LCAD antigen in the lung tissue in sudden infant death syndrome. However, the effects of the polymorphism on LCAD function has not been tested. The present work evaluated recombinant LCAD K333Q. Compared to wild-type LCAD protein, LCAD K333Q exhibited significantly reduced enzymatic activity. Molecular modeling suggested that K333 is within interacting distance of the essential FAD cofactor, and the K333Q protein showed a propensity to lose FAD. Exogenous FAD only partially rescued the activity of LCAD K333Q. LCAD K333Q protein was less stable than wild-type when incubated at physiological temperatures, likely explaining the observation of dramatically reduced LCAD antigen in primary ATII cells isolated from individuals homozygous for K333Q. Despite the effect of K333Q on activity, stability, and antigen levels, the frequency of the polymorphism was not increased among infants and children with lung disease.

Impact of Bilateral Infiltrates on Inflammatory Biomarker Levels and Clinical Outcomes of Children With Oxygenation Defect.

OBJECTIVES: The 2015 definition for pediatric acute respiratory distress syndrome did not require the presence of bilateral infiltrates. We tested the hypothesis that pediatric patients meeting oxygenation criteria for pediatric acute respiratory distress syndrome but without bilateral infiltrates would have different inflammatory biomarker levels and clinical outcomes than those with bilateral infiltrates. DESIGN: Secondary analysis of a prospective cohort study. SETTING: Twenty-two PICUs. PATIENTS: Four-hundred forty-six patients age 2 weeks to 17 years intubated for respiratory failure with oxygenation index greater than or equal to 4 or oxygenation saturation index greater than or equal to 5 on the day of intubation or the day after. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with bilateral infiltrates, either on the day of intubation or within the following 2 days, were compared with children who never developed bilateral infiltrates. Two analyses were performed to test 1) whether bilateral infiltrates are associated with elevated interleukin-1 receptor antagonist or interleukin-8 and 2) whether bilateral infiltrates are associated with worse clinical outcomes. Patients with bilateral infiltrates more often had a primary diagnosis of pneumonia (41% vs 28%; p = 0.02) and less often asthma (8% vs 23%; p < 0.01). After controlling for age, gender, and primary diagnosis, interleukin-1 receptor antagonist was higher on study days 1 and 2 in patients with bilateral infiltrates. There was no difference in interleukin-8 levels. After adjusting for age, gender, Pediatric Risk of Mortality score, and severity of oxygenation defect, presence of bilateral infiltrates was associated with longer duration of mechanical ventilation in survivors (hazard ratio, 0.64; 95% CI, 0.49-0.82; p < 0.01); this association was independent of primary diagnosis. Overall mortality was 9%; mortality was higher in those without bilateral infiltrates (14% vs 8%; p = 0.04). CONCLUSIONS: Children meeting pediatric acute respiratory distress syndrome oxygenation criteria with bilateral infiltrates on chest radiograph experience a more intense early inflammatory response. Bilateral infiltrates are associated with longer time on the ventilator independent of oxygenation defect severity.

Predicting Mortality in Children With Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

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.