Potential therapeutics in pediatric acute respiratory distress syndrome: what does the immune system have to offer? A narrative review

Since first described, acute respiratory distress syndrome (ARDS) has been understood to be an inflammatory disease with a dysregulated hyperinflammatory response. While fewer investigations have studied these phenomena in pediatric ARDS (PARDS), similar pathways are believed to be involved. Significant attention has been paid to the innate immune system, particularly neutrophils and neutrophil-related signaling, more recent studies have provided additional nuance regarding the role of upstream damage-associated molecular patterns (DAMPs) and subsequent neutrophil-mediated inflammation, lung permeability, and alveolar epithelial damage. For example, neutrophil extracellular traps (NETs) and inflammasome signaling have been identified as critical mediators existing at the junction of DAMPs and downstream inflammation. We demonstrate how the conclusions obtained from pre-clinical studies of lung injury are highly dependent upon the model chosen, and how this can lead us astray when developing therapies. More recently the adaptive immune system, specifically select T cell subpopulations, have also been implicated in ARDS. This raises the possibility of antigen-specific immunomodulation as a potential therapeutic avenue in ARDS. Finally, we briefly review randomized controlled trials attempting to manipulate the immune dysregulation in ARDS, including pleiotropic immunomodulators like corticosteroids and interferon-β, and what these studies can teach us about the design of novel therapeutics and the design of future trials.