Objectives: Much of the research related to pediatric acute respiratory distress syndrome has focused on inhospital mortality and interventions affecting this outcome. Limited data exist on survivors’ morbidity, hospital disposition, and 1-year survival. The aim of this study was to determine new morbidity rate, discharge disposition, and 1-year mortality for survivors of pediatric acute respiratory distress syndrome. Design: Secondary analysis of prospective cohort study. Setting: Quaternary children’s hospital. Patients: Three-hundred sixteen mechanically ventilated children with pediatric acute respiratory distress syndrome (Berlin and Pediatric Acute Lung Injury Consensus Conference criteria) between July 2011 and December 2014. Interventions: None. Measurements and Main Results: We performed secondary analysis of a prospectively recruited cohort of 316 mechanically ventilated children with pediatric acute respiratory distress syndrome between July 2011, and December 2014. Preillness and hospital discharge Functional Status Scale score were determined via chart review, and factors associated with new morbidity, defined as an increase of Functional Status Scale score of 3 or more, were analyzed. Demographic variables, pediatric acute respiratory distress syndrome characteristics, and ventilator management were tested for association with development of new morbidity, discharge disposition, and 1-year mortality. Inhospital mortality of pediatric acute respiratory distress syndrome was 13.3% (42/316). Of 274 survivors to hospital discharge, new morbidity was seen in 63 patients (23%). Discharge to rehabilitation rate was 24.5% (67/274) and associated with development of new morbidity. One- and 3-year mortality of survivors was 5.5% (15 deaths) and 8% (22 deaths) and was associated with baseline Functional Status Scale, immunocompromised status, Pediatric Risk of Mortality III, and organ failures at pediatric acute respiratory distress syndrome onset, but not with pediatric acute respiratory distress syndrome severity. Conclusions: New morbidity was common after pediatric acute respiratory distress syndrome and appears to be intermediate phenotype between survival without morbidity and death, making it a useful metric in future interventional and outcome studies in pediatric acute respiratory distress syndrome.

BACKGROUND: The molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS). METHODS: In a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models. RESULTS: In 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality. CONCLUSIONS: Pediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS. FUNDING: NIH (K23HL-136688, R01-HL148054).

The hallmarks of pediatric acute respiratory failure (ARF) are dysregulated inflammation and surfactant dysfunction. The objective is to study association of surfactant protein (SP) genes’ single nucleotide polymorphisms (SNPs) with ARF and its morbidity: pulmonary dysfunction at discharge (PDAD), employing a single-, two-, and three-SNP interaction model. We enrolled 468 newborn controls and 248 children aged ≤ 24 months with ARF; 86 developed PDAD. Using quantitative genetic principles, we tested the association of SP genes SNPs with ARF and PDAD. We observed a dominant effect of rs4715 of the SFTPC on ARF risk. In a three-SNP model, we found (a) 34 significant interactions among SNPs of SFTPA1, SFTPA2, and SFTPC associated with ARF (p = 0.000000002–0.05); 15 and 19 of those interactions were associated with increased and decreased risk for ARF, respectively; (b) intergenic SNP–SNP interactions of both hydrophobic and hydrophilic SP genes associated with PDAD (p = 0.00002–0.03). The majority of intra- and intergenic interactions associated with ARF involve the SFTPA2 SNPs, whereas most of the intra- and intergenic interactions associated with PDAD are of SFTPA1 SNPs. We also observed a dominant effect of haplotypes GG of SFTPA1 associated with increased and AA of SFTPC associated with decreased ARF risk (p = 0.02). To the best of our knowledge, this is the first study showing an association of complex interactions of SP genes with ARF and PDAD. Our data indicate that SP genes polymorphisms may contribute to ARF pathogenesis and subsequent PDAD and/or may serve as markers for disease susceptibility in healthy children.

Objectives: Acute respiratory failure is a common reason for admission to PICUs. Short- and long-term effects on pulmonary health in previously healthy children after acute respiratory failure requiring mechanical ventilation are unknown. The aim was to determine if clinical course or characteristics of mechanical ventilation predict persistent respiratory morbidity at follow-up. Design: Prospective cohort study with follow-up questionnaires at 6 and 12 months. Setting: Ten U.S. PICUs. Patients: Two-hundred fifty-five children were included in analysis after exclusion for underlying chronic disease or incomplete data. One-hundred fifty-eight and 130 children had follow-up data at 6 and 12 months, respectively. Interventions: None. Measurements and Main Results: Pulmonary dysfunction at discharge a priori defined as one of: mechanical ventilation, supplemental oxygen, bronchodilators or steroids at 28 days or discharge. Persistent respiratory morbidity a priori defined as a respiratory PedsQL, a pediatric quality of life measure, greater than or equal to 5 or asthma diagnosis, bronchodilator or inhaled steroids, or unscheduled clinical evaluation for respiratory symptoms. Multivariate backward stepwise regression using Akaike information criterion minimization determined independent predictors of these outcomes. Pulmonary dysfunction at discharge was present in 34% of patients. Positive bacterial respiratory culture predicted pulmonary dysfunction at discharge (odds ratio, 4.38; 95% CI, 1.66–11.56). At 6- and 12-month follow-up 42% and 44% of responders, respectively, had persistent respiratory morbidity. Pulmonary dysfunction at discharge was associated with persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months was strongly predictive of 12-month persistent respiratory morbidity (odds ratio, 18.58; 95% CI, 6.68–52.67). Positive bacterial respiratory culture remained predictive of persistent respiratory morbidity in patients at both follow-up points. Conclusions: Persistent respiratory morbidity develops in up to potentially 44% of previously healthy children less than or equal to 24 months old at follow-up after acute respiratory failure requiring mechanical ventilation. This is the first study, to our knowledge, to suggest a prevalence of persistent respiratory morbidity and the association between positive bacterial respiratory culture and pulmonary morbidity in a population of only previously healthy children with acute respiratory failure.

Excess mortality risk imparted by acute respiratory failure in children is unknown. We determined excess mortality risk associated with mechanically ventilated acute respiratory failure in pediatric sepsis. Novel ICD10-based algorithms were derived and validated to identify a surrogate for acute respiratory distress syndrome to calculate excess mortality risk. Algorithm-identified ARDS was identified with specificity of 96.7% (CI 93.0 − 98.9) and sensitivity of 70.5% (CI 44.0 – 89.7). Excess risk of mortality for ARDS was 24.4% (CI 22.9 – 26.2). Development of ARDS requiring mechanical ventilation imparts modest excess risk of mortality in septic children.