Pathogenesis of COVID-19-induced ARDS: implications for an aging population

Torres Acosta, Manuel A.; Singer, Benjamin D.

The coronavirus disease (COVID)-19 pandemic has elicited a swift response by the scientific community to elucidate the pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV)-2-induced lung injury and develop effective therapeutics. Clinical data indicate that severe COVID-19 most commonly manifests as viral pneumonia-induced acute respiratory distress syndrome (ARDS), a clinical entity mechanistically understood best in the context of influenza A virus-induced pneumonia. Similar to influenza, advanced age has emerged as the leading host risk factor for developing severe COVID-19. In this review we connect the current understanding of the SARS-CoV-2 replication cycle and host response to the clinical presentation of COVID-19, borrowing concepts from influenza A virus-induced ARDS pathogenesis and discussing how these ideas inform our evolving understanding of COVID-19-induced ARDS. We also consider important differences between COVID-19 and influenza, mainly COVID-19's protean clinical presentation and associated lymphopenia, the contrasting role of interferon-γ in mediating the host immune response to these viruses, and SARS-CoV-2's tropism for vascular endothelial cells, commenting on the potential limitations of influenza as a model for COVID-19. Finally, we explore hallmarks of aging that could explain the association between advanced age and susceptibility to severe COVID-19.