Single Cell Analysis Identifies Distinct Profiles in Pediatric Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS), termed pediatric ARDS (pARDS) in children, is a severe form of acute respiratory failure (ARF) that is associated with significant morbidity and mortality. Pathologic immune responses have been implicated in the development of pARDS. Here, we present a unique description of microbial sequencing and single cell gene expression in tracheal aspirates (TAs) obtained longitudinally from infants admitted to the pediatric intensive care unit (PICU) with ARF. Important alterations in TA epithelial cell, mononuclear phagocyte (MNP), and neutrophil transcription were associated with subjects' illness severity, etiology (of ARF), and sampling time point. Specifically, in patients with moderate to severe pARDS compared to those with no to mild pARDS we identified reduced interferon stimulated gene (ISG) expression, altered MNP transcriptional programs, and progressive airway neutrophilia associated with a unique transcriptional profile in aged neutrophils. We go on to identify Folate Receptor 3 (Gamma; FOLR3) as a neutrophil product enriched in patients with moderate or severe pARDS. Our findings indicate that pARDS is defined by distinct inflammatory cell profiles that are etiology- and severity-dependent and implicate inadequate induction of ISGs, altered repair-associated macrophage transcriptional programs, and accumulation of aged neutrophils in the airways in the pathogenesis of moderate to severe pARDS caused by RSV.