Circulating nucleosomes are associated with mortality in pediatric acute respiratory distress syndrome

Abstract

Nucleosome levels were not associated with either Berlin (P ϭ 0.845) or PALICC (P ϭ 0.886) oxygenation categories, nor with etiology of PARDS (P ϭ 0.527). Nucleosomes were correlated with increasing numbers of nonpulmonary organ failures (P ϭ 0.009 for trend), and were higher in patients whose PaO 2 /FiO 2 worsened (P ϭ 0.012) over the first 72 h of PARDS. In regression analysis, nucleosome levels were independently associated with mortality after adjusting for either age, severity of illness score, number of nonpulmonary organ failures, vasopressor score, or Pa O 2 /FiO 2 (all P Ͻ 0.05). In conclusion, plasma nucleosome levels in early PARDS were associated with increased mortality, correlated with number of nonpulmonary organ failures, and preceded worsening oxygenation. The potential utility of this biomarker for prognostication, risk stratification, and mechanistic insight should be investigated further.acute respiratory distress syndrome; ARDS; pediatric acute respiratory distress syndrome; PARDS; nucleosomes MECHANISMS UNDERLYING pediatricacute respiratory distress syndrome (PARDS) remain elusive. While PARDS was historically defined by adult ARDS criteria (6, 25), it possesses a distinct epidemiologic, comorbidity, and outcome profile, prompting the Pediatric Acute Lung Injury Consensus Conference (PALICC) to develop pediatric-specific definitions in 2015 (23). Among other differences, the PALICC definition of PARDS uses oxygenation index (OI), rather than Pa O 2 /Fi O 2 , for risk stratification, despite the inconsistent relationship between oxygenation and outcome (1, 31). Common to both adult (35, 36) and pediatric (13, 39) ARDS is the significance of nonpulmonary organ failures as a predictor of poor outcome. While several investigations have focused on the systemic inflammatory response and the associated neutrophil activation and cytokine release (9, 36), the pathogenic mechanisms invoked remain incomplete for explaining the development of lung injury and multisystem organ failure (MSOF).Recent studies in adult ARDS have implicated circulating nucleosomes, the histone/DNA complexes resulting from nuclear chromatin degradation released after cellular damage, as potentially pathogenic in sepsis (4, 12, 24, 38), aspiration (41), and trauma-related ARDS (2). Normally located within the nucleus, nucleosomes released into the circulation act as damage-associated molecular patterns (DAMP), and have been shown to be toxic to multiple cell types (2,12,24), offering a novel mechanism linking diverse inciting insults with subsequent lung injury and organ failure. However, whether nucleosomes are associated with PARDS development or progression is unknown.Rapid identification of children with PARDS who are most at risk of a poor outcome is essential for accurate risk stratification in clinical trials, as it allows redirection of aggressive interventions toward the sickest cohort. Unlike adult ARDS, few studies address the utility of biomarkers in PARDS. The reduced incidence of PARDS [12.8 per 100,000 person-ye...

Recent Advances in Pediatric Acute Respiratory Distress Syndrome (PARDS)

“…The association of nucleosome levels and mortality was independent of age, severity of illness, number of non-pulmonary organ failures, vasopressor score, or PaO 2 /FiO 2 in regression analysis. There was no association with nucleosome levels and etiology of ARDS, nor was there an association with severity of illness as defined by Berlin or PALICC oxygenation categories [11].…”

Endothelial Biomarkers Are Associated With Indirect Lung Injury in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome

“…We conducted a secondary analysis of prospectively collected plasma from a cohort of pediatric patients with ARDS admitted to the PICU of a single academic children’s hospital (CHOP). Participants had been enrolled in one of two prospective observational parent studies of pediatric sepsis ( 15 ) and ARDS ( 4 , 16 ) between May 2014 and January 2018.…”

Peripheral blood transcriptomic sub-phenotypes of pediatric acute respiratory distress syndrome

“…This was a prospective cohort study approved by the Children’s Hospital of Philadelphia’s (CHOP) Institutional Review Board between January 1, 2018, and June 30, 2019, with informed consent obtained prior to enrollment [ 21 , 22 ]. Inclusion criteria were (1) acute (≤ 7 days of risk factor) respiratory failure requiring invasive mechanical ventilation, (2) arterial access, (3) age > 1 month and < 18 years, (4) P a o 2 /F io 2 ≤ 300 on two consecutive arterial blood gases separated by ≥ 1 h on positive end-expiratory pressure (PEEP) ≥ 5 cm h 2 o , and (5) bilateral infiltrates on radiograph.…”