Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Eddins, Devon J.; Yang, Junkai; Kosters, Astrid; Giacalone, Vincent D.; Pechuan, Ximo; Chandler, Joshua D.; Eum, Jinyoung; Babcock, Benjamin R.; Dobosh, Brian S.; Hernández, Mindy R.; Abdulkhader, Fathma; Collins, Genoah L.; Ramonell, Richard P.; Moussion, Christine; Orlova, Darya Y.; Sanz, Ignacio; Lee, F. Eun-Hyung; Tirouvanziam, Rabindra M.; Ghosn, Eliver E.B.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused ∼40 million cases and over 648,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African-American (AA) patients in some areas, yet targeted studies within this demographic are scant. Multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed low viral load, yet pronounced and persistent pulmonary neutrophilia with advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS), including exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Circulating S100A12+/IFITM2+ mature neutrophils are recruited via the IL-8/CXCR2 axis, which emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19. Graphical Abstract The lung pathology due to severe COVID-19 is marked by a perpetual pathogenic neutrophilia, leading to acute respiratory distress syndrome (ARDS) even in the absence of viral burden. Circulating mature neutrophils are recruited to the airways via IL-8 (CXCL8)/CXCR2 chemotaxis. Recently migrated neutrophils further differentiate into a transcriptionally active and hyperinflammatory state, with an exacerbated expression of IL-8 (CXCL8), IL-1β (IL1B), CCL3, CCL4, neutrophil elastase (NE), and myeloperoxidase (MPO) activity. Airway neutrophils and recruited inflammatory monocytes further increase their production of IL-8 (CXCL8), perpetuating lung neutrophilia in a feedforward loop. MdCs and T cells produce IL-1β and TNF, driving neutrophils reprogramming and survival.