Immunocompromised Children With Acute Respiratory Distress Syndrome Possess a Distinct Circulating Inflammatory Profile

Abstract

IMPORTANCE:Immunocompromised status, with and without stem cell transplant, confers a worse prognosis in pediatric acute respiratory distress syndrome. An improved understanding of the biochemical profile of immunocompromised children with acute respiratory distress syndrome would inform whether specific pathways are targetable, or merely bystanders, in order to improve outcomes in this high-risk subgroup. OBJECTIVES:We aimed to identify a biomarker profile of immunocompromised children, with and without stem cell transplant, independent of illness severity. DESIGN, SETTINGS, AND PARTICIPANTS:This was a secondary analysis of a prospective cohort study of intubated children with Berlin-defined acute respiratory distress syndrome with existing biomarker measurements conducted in a large academic PICU between 2014 and 2019. MAIN OUTCOMES AND MEASURES:Biomarker levels were compared between immunocompetent and immunocompromised children, with and without stem cell transplant, both prior to and after adjusting for severity of illness. RESULTS:In 333 children with acute respiratory distress syndrome, 84 were immunocompromised, of whom 39 had a stem cell transplant. Circulating neutrophil levels were strongly correlated with biomarkers, with 14 of 18 measured proteins differentially expressed in patients with versus without neutropenia. In order to identify biomarker levels independent of severity of illness, acute respiratory distress syndrome etiology, and neutrophil levels, we computed predicted (log-transformed) biomarker levels after adjusting for confounders using linear regression and then compared these severity-adjusted levels between immunocompetent and immunocompromised (with and without stem cell transplant) subjects using analyses of variance and post hoc Bonferroni. After multivariable adjustment, 11 biomarkers were higher in immunocompromised subjects without stem cell transplant, relative to immunocompetent, implicating endotheliopathy (angiopoietin-2), tissue damage (procollagen type III N-terminal peptide), and innate immunity. A single biomarker, C-C motif chemokine ligand 22, was lower in immunocompromised subjects with and without stem cell transplant. CONCLUSIONS AND RELEVANCE:Immunocompromised children with acute respiratory distress syndrome were characterized by elevations in pro-inflammatory and endothelial damage biomarkers. Our study provides insight into mechanisms underlying the molecular heterogeneity of this population and potentially identifies targetable pathways to mitigate their increased mortality risk.

Endothelial Glycocalyx Degradation Patterns in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome: A Single Center Retrospective Observational Study

“…However, our associations were maintained even after adjustment for confounders and removal of immunocompromised patients, a group that when suffering from PARDS may be associated with a higher susceptibility to and degree of endothelial injury. 52,53 Taken together, these results suggest that EGCX degradation as reflected by increased concentrations of highly sulfated HS disaccharides and syndecan-1 may be in part associated with the sepsis-associated PARDS pathobiology. There remains an incomplete understanding of the key inflection points that mediate pulmonary microvascular endothelial dysfunction supporting an ongoing need to study the mechanistic role of EGCX degradation in children with PARDS.…”

“…However, our associations were maintained even after adjustment for confounders and removal of immunocompromised patients, a group that when suffering from PARDS may be associated with a higher susceptibility to and degree of endothelial injury. 52 , 53 …”

Prone position in the mechanical ventilation of acute respiratory distress syndrome children: a systematic review and meta-analysis

“…During prone ventilation, the negative pressure in the thoracic cavity gradually decreased from the dorsal to the ventral, while the transpulmonary pressure decreased, resulting in a decrease in ventral ventilation, but it could still maintain the opening of ventral alveoli ( 30 ). At the same time, after the prone position, the lung lobe volume slightly increased compared with the supine position, the original anatomical position is located below the heart compressed by the heart to reduce the lung lobe volume increased, thus causing the collapse alveoli originally oppressed by the heart to re-expand ( 31 ). Through the comparison of lung tissue ventilation blood flow gradient between healthy volunteers and mechanically ventilated patients in different positions, it has been confirmed that the ventilation distribution increase slowly from ventral lung tissue to back when lying on the back, and suddenly decreased at the last 25% of the dorsal lung tissue.…”

Diagnostic yield of bronchoscopy in children with leukemia or post hematopoietic stem cell transplant

“…The biology of respiratory failure in immunocompromised children is complex. There have been efforts to identify underlying biomarkers in this population, which is a step toward better understanding the biologic causes 23,24 . However, currently bronchoscopy with extensive infectious workup and clinical expertise are the only widely available methods to diagnose causes of pulmonary complications.…”